Compounds for the reduction of beta-amyloid production

ABSTRACT

The present disclosure provides a series of compounds of the formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             which modulate β-amyloid peptide (β-AP) production and are useful in the treatment of Alzheimer&#39;s Disease and other conditions affected by β-amyloid peptide (β-AP) production.

CROSS REFERENCE TO RELATED APPLICATION

The present application claims the benefit of U.S. provisionalapplication Ser. No. 61/324,201 filed Apr. 14, 2010 and U.S. provisionalapplication Ser. No. 61/230,202 filed Jul. 31, 2009, the contents ofwhich are herein incorporated by reference.

FIELD OF THE INVENTION

The present disclosure relates to methods of treating Alzheimer'sDisease (AD) and other conditions related to β-amyloid production usingcompounds which are inhibitors of β-amyloid peptide (Aβ) production. Thedisclosure further relates to pharmaceutical compositions comprisingthese compounds.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a progressive neurodegenerative diseasewhich begins with memory loss and progresses to include severe cognitiveimpairment, altered behavior, and decreased motor function (Grundman, M.et al., Arch Neurol. (2004) 61: 59-66; Walsh, D. M. et al., Neuron(2004) 44: 181-193). It is the most common form of dementia andrepresents the third leading cause of death after cardiovasculardisorders and cancer. The cost of AD is enormous and includes thesuffering of the patients and families and the lost productivity ofpatients and caregivers. No treatment that effectively prevents AD orreverses the clinical symptoms and underlying pathophysiology iscurrently available.

A definitive diagnosis of AD for a demented patient requires ahistopathological evaluation of the number and localization of neuriticplaques and neurofibrillary tangles upon autopsy (Consensusrecommendations for the postmortem diagnosis of Alzheimer's disease.Neurobiol Aging (1997) 18: S1-2). Similar alterations are observed inpatients with Trisomy 21 (Down syndrome). Plaques primarily consist ofβ-amyloid (Aβ) peptides that are formed by a stepwise proteolyticcleavage of the amyloid precursor protein (APP) by β-site APP-cleavingenzyme (BACE), to generate the N-terminus, and γ-secretase, to generatethe C-terminus (Selkoe, D. J., Physiol Rev. (2001) 81: 741-766).γ-Secretase is a transmembrane protein complex that includes Nicastrin,Aph-1, PEN-2, and either Presenilin-1 (PS-1) or Presenilin-2 (PS-2)(Wolfe, M. S. et al., Science (2004) 305: 1119-1123). PS-1 and PS-2 arebelieved to contain the catalytic sites of γ-secretase.

Aβ40 is the most abundant form of AP synthesized (80-90%), while Aβ42 ismost closely linked with AD pathogenesis. In particular, mutations inthe APP, PS-1, and PS-2 genes that lead to rare, familial forms of ADimplicate Aβ42 aggregates as the primary toxic species (Selkoe, D. J.,Physiol Rev., (2001) 81: 741-766). Current evidence suggests thatoligomeric, protofibrillar and intracellular Aβ42 play a significantrole in the disease process (Cleary, J. P. et al., Nat. Neurosci. (2005)δ: 79-84). Inhibitors of the enzymes that form Aβ42, such asγ-secretase, represent potential disease-modifying therapeutics for thetreatment of AD.

Evidence suggests that a reduction in brain AP levels by inhibition ofγ-secretase may prevent the onset and progression of AD (Selkoe, D.Physiol. Rev. (2001) 81: 741-766; Wolfe, M., J. Med. Chem. (2001) 44:2039-2060). There are emerging data for the role of AP in otherdiseases, including mild cognitive impairment (MCI), Down syndrome,cerebral amyloid angiopathy (CAA), dementia with Lewy bodies (DLB),amyotrophic lateral sclerosis (ALS-D), inclusion body myositis (IBM),and age-related macular degeneration. Advantageously, compounds thatinhibit γ-secretase and reduce production of AP could be used to treatthese or other AP-dependent diseases.

Excess production and/or reduced clearance of AP causes CAA (Thal, D. etal., J. Neuropath. Exp. Neuro. (2002) 61: 282-293). In these patients,vascular amyloid deposits cause degeneration of vessel walls andaneurysms that may be responsible for 10-15% of hemorrhagic strokes inelderly patients. As in AD, mutations in the gene encoding AP lead to anearly onset form of CAA, referred to as cerebral hemorrhage withamyloidosis of the Dutch type, and mice expressing this mutant proteindevelop CAA that is similar to patients. Compounds that reduce Aβ levelscould reduce or prevent CAA.

DLB manifests with visual hallucinations, delusions, and parkinsonism.Interestingly, familial AD mutations that cause Aβ deposits can alsocause Lewy bodies and DLB symptoms (Yokota, O. et al., Acta Neuropathol(Berl) (2002) 104: 637-648). Further, sporadic DLB patients have Aβdeposits similar to those in AD (Deramecourt, V. et al., J NeuropatholExp Neurol (2006) 65: 278-288). Based on this data, AP likely drivesLewy body pathology in DLB and, therefore, compounds that reduce Aβlevels could reduce or prevent DLB.

Approximately 25% of ALS patients have significant dementia or aphasia(Hamilton, R. L. et al., Acta Neuropathol (Berl) (2004) 107: 515-522).The majority (−60%) of these patients, designated ALS-D, containubiquitin-positive inclusions comprised primarily of the TDP-43 protein(Neumann, M. et al., Science (2006) 314: 130-133). About 30% of theALS-D patients have amyloid plaques consistent with Aβ causing theirdementia (Hamilton, R. L. et al., Acta Neuropathol (Berl) (2004) 107:515-522). These patients should be identifiable with amyloid imagingagents and potentially could be treated by compounds that reduce Aβlevels.

IBM is a rare, age-related degenerative disease of skeletal muscle. Theappearance of Aβ deposits in IBM muscle and the recapitulation ofseveral aspects of the disease by directing APP overexpression to musclein transgenic mice support the role of Aβ in IBM (reviewed in Murphy, M.P. et al., Neurology (2006) 66: S65-68). Compounds that reduce Aβ levelscould reduce or prevent IBM.

In age-related macular degeneration, Aβ was identified as one of severalcomponents of drusen, extracellular deposits beneath the retinal pigmentepithelium (RPE) (Anderson, D. H. et al., Exp Eye Res (2004) 78:243-256). A recent study has shown potential links between Aβ andmacular degeneration in mice (Yoshida, T. et al., J Clin Invest (2005)115: 2793-2800). Increases in Aβ deposition and supranuclear cataractshave been found in AD patients (Goldstein, L. E. et al., Lancet (2003)361: 1258-1265). Compounds that reduce Aβ levels could reduce or preventage-related macular degeneration.

Compounds which inhibit gamma secretase may also be useful in treatingconditions associated with loss of myelination, for example multiplesclerosis (Watkins, T. A., et al., Neuron (2008) 60: 555-569).

A recent study by Georgetown University Medical Center researcherssuggests that gamma-secretase inhibitors may prevent long-term damagefrom traumatic brain injury (Loane, D. J., et al., Nature Medicine(2009): 1-3).

A logical approach to reducing Aβ levels is to block the action of thesecretases. A complementary approach is to selectively reduce productionof Aβ1-42 by the action of certain compounds that serve to direct theγ-secretase-mediated cleavage of APP to instead produce shorter forms ofAβ. These shorter forms appear to aggregate less easily and solutions ofthe shorter forms of Aβ are less neurotoxic than solutions of Aβ1-42(See Barten, Donna M.; Meredith, Jere E., Jr.; Zaczek, Robert; Houston,John G.; Albright, Charles F. Drugs in R&D (2006), 7(2), 87-97). Thus,compounds that selectively reduce Aβ1-42 production and theirpharmaceutical compositions are beneficial agents that will preventdamage from overproduction of Aβ and are useful in treating Alzheimer'sdisease, Down syndrome, CAA, and inclusion body myositis, DLB, and otherdisorders where Aβ is overproduced.

SUMMARY OF THE INVENTION

In its first aspect the present disclosure provides a compound offormula (I)

or a pharmaceutically acceptable salt thereof, wherein

A is a five- or six-membered heteroaromatic ring containing from one tothree heteroatoms independently selected from nitrogen, oxygen, andsulfur; wherein said heteroaromatic ring is optionally substituted withone or two groups selected from halo, hydroxy, amino, C₁₋₆alkoxy, andC₁₋₆alkyl;

B is selected from phenyl and pyridinyl, wherein the phenyl andpyridinyl are optionally substituted with one or two substituentsindependently selected from C₁₋₆alkoxy, C₁₋₃alkylamino-C₁₋₆alkoxy,cyano, C₁₋₃dialkylamino-C₁₋₆alkoxy, halo, haloC₁₋₆alkoxy, hydroxy,methylamino, and amino;

D is selected from

“

” denotes the point of attachment to the nitrogen atom of the parentmolecule;

“

” denotes the point of attachment to the ‘E’ moiety;

R^(a) is selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, and hydroxy;

R^(b) is —NR^(x)R^(y), wherein R^(x) and R^(y) are independentlyselected from hydrogen, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkoxycarbonyl, C₁₋₆alkyl, C₃₋₇cycloalkyl,(C₃₋₇cycloalkyl)C₁₋₄alkyl, hydroxyC₁₋₄alkyl, and trideuteromethyl,wherein the alkyl part of the (C₃₋₇cycloalkyl)C₁₋₄alkyl can beoptionally substituted with a C₁₋₄alkoxy group; or, R^(x) and R^(y),together with the nitrogen atom to which they are attached, form a four-to seven-membered monocyclic or bicyclic ring optionally containing onedouble bond and optionally containing one additional heteroatom selectedfrom O, NR^(z), and S; wherein R^(z) is selected from hydrogen,C₁₋₆alkyl, and

C₁₋₄alkoxycarbonyl; and wherein the ring is optionally substituted withone or two substituents independently selected from C₁₋₆alkoxy,C₁₋₆alkyl, halo, haloC₁₋₄alkyl, hydroxy, —NR^(f)R^(g), oxo, spirocyclicdioxolanyl; wherein R^(f) and R^(g) are independently selected fromhydrogen, C₁₋₄alkoxycarbonyl, and C₁₋₆alkyl;

R^(c) is selected from hydrogen, C₁₋₄alkylsulfonyl,C₁₋₄alkylsulfonylamido, amino, C₁₋₆alkylamino, C₁₋₆dialkylamino,C₃₋₇cycloalkylamino, hydroxy, and C₁₋₄alkoxy;

R^(d) is selected from hydrogen, C₁₋₆alkyl, C₁₋₄alkoxyC₁₋₄alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl,C₃₋₇cycloalkylsulfonyl, C₃₋₇cycloalkylcarbonyl,C₁₋₆dialkylaminoC₁₋₄alkylcarbonyl, and haloC₁₋₄alkyl, wherein the alkylpart of the alkoxycarbonyl, the alkylcarbonyl, and the alkylsulfonyl areoptionally substituted with one substituent selected fromC₁₋₄dialkylamino, and C₁₋₄alkoxy; and

E is selected from C₁₋₆alkyl, C₄₋₆cycloalkyl, (C₄₋₇cycloalkyl)C₁₋₄alkyl,benzyl, phenyl, and a five- to six-membered heteroaromatic ringcontaining one or two nitrogen atoms, wherein the phenyl, the phenylpart of the benzyl, and the heteroaromatic ring are each optionallysubstituted with one, two, or three substituents independently selectedfrom C₁₋₆alkyl, C₁₋₆alkoxy, cyano, halo, halo C₁₋₆alkoxy, andhaloC₁₋₆alkyl.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

In a first embodiment of the first aspect the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as set forth above wherein A is a five-memberedheteroaromatic ring containing from one to three nitrogen atoms; andwherein said heteroaromatic ring is optionally substituted with onegroup selected from halo and C₁₋₆alkyl. In a second embodiment, B isselected from phenyl and pyridinyl, wherein the phenyl and pyridinyl areoptionally substituted with one or two substituents independentlyselected from C₁₋₆alkoxy and halo. In a third embodiment, E is phenyloptionally substituted with one, two, or three substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, cyano, halo,haloC₁₋₆alkoxy, and haloC₁₋₆alkyl. In a fourth embodiment, D is selectedfrom

In a fifth embodiment, R^(b) is —NR^(x)R^(y), wherein R^(x) and R^(y)are independently selected from hydrogen, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₆alkyl, C₃₋₇cycloalkyl, hydroxyC₁₋₄alkyl, and trideuteromethyl,wherein the alkyl part of the (C₃₋₇cycloalkyl)C₁₋₄alkyl can beoptionally substituted with a C₁₋₄alkoxy group.

In a sixth embodiment of the first aspect, the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

A is a five-membered heteroaromatic ring containing from one to threenitrogen atoms; wherein said heteroaromatic ring is optionallysubstituted with one group selected from halo and C₁₋₆alkyl;

B is selected from phenyl and pyridinyl, wherein the phenyl andpyridinyl are optionally substituted with one or two substituentsindependently selected from C₁₋₆alkoxy and halo;

E is phenyl optionally substituted with one, two, or three substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, cyano, halo,haloC₁₋₆alkoxy, and haloC₁₋₆alkyl;

D is selected from

and

R^(b) is —NR^(x)R^(y), wherein R^(x) and R^(y), together with thenitrogen atom to which they are attached, form a four- to seven-memberedmonocyclic or bicyclic ring optionally containing one additionalheteroatom selected from O and NR^(z); wherein R^(z) is selected fromC₁₋₆alkyl, and C₁₋₄alkoxycarbonyl; and wherein the ring is optionallysubstituted with one or two substituents independently selected fromC₁₋₆alkoxy, C₁₋₆alkyl, halo, haloC₁₋₄alkyl, hydroxy, —NR^(f)R^(g), oxo,and spirocycle dioxolanyl; wherein R^(f) and R^(g) are independentlyselected from hydrogen, C₁₋₄alkoxycarbonyl, and C₁₋₆alkyl.

In a seventh embodiment of the first aspect, the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

A is a five-membered heteroaromatic ring containing from one to threenitrogen atoms; wherein said heteroaromatic ring is optionallysubstituted with one group selected from halo and C₁₋₆alkyl;

B is selected from phenyl and pyridinyl, wherein the phenyl andpyridinyl are optionally substituted with one or two substituentsindependently selected from C₁₋₆alkoxy and halo;

E is phenyl optionally substituted with one, two, or three substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, cyano, halo,haloC₁₋₆alkoxy, and haloC₁₋₆alkyl; and

D is selected from

In an eighth embodiment of the first aspect, the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

A is a five-membered heteroaromatic ring containing from one to threenitrogen atoms; wherein said heteroaromatic ring is optionallysubstituted with one group selected from halo and C₁₋₆alkyl;

B is selected from phenyl and pyridinyl, wherein the phenyl andpyridinyl are optionally substituted with one or two substituentsindependently selected from C₁₋₆alkoxy and halo;

E is phenyl optionally substituted with one, two, or three substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, cyano, halo,haloC₁₋₆alkoxy, and haloC₁₋₆alkyl;

D is selected from

and

R^(b) is —NR^(x)R^(y), wherein R^(x) and R^(y) are independentlyselected from hydrogen, C₁₋4alkoxyC₁₋₄alkyl, C₁₋₆alkyl, C₃₋₇cycloalkyl,hydroxyC₁₋₄alkyl, and trideuteromethyl, wherein the alkyl part of the(C₃₋₇cycloalkyl)C₁₋₄alkyl can be optionally substituted with aC₁₋₄alkoxy group.

In a ninth embodiment of the first aspect, the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

A is a five-membered heteroaromatic ring containing from one to threenitrogen atoms; wherein said heteroaromatic ring is optionallysubstituted with one group selected from halo and C₁₋₆alkyl;

B is selected from phenyl and pyridinyl, wherein the phenyl andpyridinyl are optionally substituted with one or two substituentsindependently selected from C₁₋₆alkoxy and halo;

E is phenyl optionally substituted with one, two, or three substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, cyano, halo,haloC₁₋₆alkoxy, and haloC₁₋₆alkyl;

D is selected from

and

R^(b) is —NR^(x)R^(y), wherein R^(x) and R^(y), together with thenitrogen atom to which they are attached, form a four- to seven-memberedmonocyclic or bicyclic ring optionally containing one additionalheteroatom selected from O and NR^(z); wherein R^(z) is selected fromC₁₋₆alkyl, and C₁₋₄alkoxycarbonyl; and wherein the ring is optionallysubstituted with one or two substituents independently selected from

C₁₋₆alkoxy, C₁₋₆alkyl, halo, haloC₁₋₄alkyl, hydroxy, —NR^(f)R^(g), oxo,and spirocycle dioxolanyl; wherein R^(f) and R^(g) are independentlyselected from hydrogen, C₁₋₄alkoxycarbonyl, and C₁₋₆alkyl.

In a tenth embodiment of the first aspect, the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

A is a five-membered heteroaromatic ring containing from one to threenitrogen atoms; wherein said heteroaromatic ring is optionallysubstituted with one group selected from halo and C₁₋₆alkyl;

B is selected from phenyl and pyridinyl, wherein the phenyl andpyridinyl are optionally substituted with one or two substituentsindependently selected from C₁₋₆alkoxy and halo;

E is phenyl optionally substituted with one, two, or three substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, cyano, halo,haloC₁₋₆alkoxy, and haloC₁₋₆alkyl; and

D is selected from

In an eleventh embodiment of the first aspect, the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

A is a five-membered heteroaromatic ring containing from one to threenitrogen atoms; wherein said heteroaromatic ring is optionallysubstituted with one group selected from halo and C₁₋₆alkyl;

B is selected from phenyl and pyridinyl, wherein the phenyl andpyridinyl are optionally substituted with one or two substituentsindependently selected from C₁₋₆alkoxy and halo;

E is phenyl optionally substituted with one, two, or three substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, cyano, halo,haloC₁₋₆alkoxy, and haloC₁₋₆alkyl;

D is selected from

and

R^(b) is —NR^(x)R^(y), wherein R^(x) and R^(y) are independentlyselected from hydrogen, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₆alkyl, C₃₋₇cycloalkyl,hydroxyC₁₋₄alkyl, and trideuteromethyl, wherein the alkyl part of the(C₃₋₇cycloalkyl)C₁₋₄alkyl can be optionally substituted with aC₁₋₄alkoxy group.

In a twelfth embodiment of the first aspect, the present disclosureprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof, wherein:

A is a five-membered heteroaromatic ring containing from one to threenitrogen atoms; wherein said heteroaromatic ring is optionallysubstituted with one group selected from halo and C₁₋₆alkyl;

B is selected from phenyl and pyridinyl, wherein the phenyl andpyridinyl are optionally substituted with one or two substituentsindependently selected from C₁₋₆alkoxy and halo;

E is phenyl optionally substituted with one, two, or three substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, cyano, halo,haloC₁₋₆alkoxy, and haloC₁₋₆alkyl;

D is selected from

and

R^(b) is —NR^(x)R^(y), wherein R^(x) and R^(y), together with thenitrogen atom to which they are attached, form a four- to seven-memberedmonocyclic or bicyclic ring optionally containing one additionalheteroatom selected from O and NR^(z); wherein R^(z) is selected fromC₁₋₆alkyl, and C₁₋₄alkoxycarbonyl; and wherein the ring is optionallysubstituted with one or two substituents independently selected from

C₁₋₆alkoxy, C₁₋₆alkyl, halo, haloC₁₋₄alkyl, hydroxy, —NR^(f)R^(g), oxo,and spirocycle dioxolanyl; wherein R^(f) and R^(g) are independentlyselected from hydrogen, C₁₋₄alkoxycarbonyl, and C₁₋₆alkyl.

In a thirteenth embodiment of the first aspect, the definition of A isexpanded to also include acyl, acetyl, nitrile, CF₃, bromo, and CH₂CN;and the heteroaromatic ring may be additionally substituted with CHCF₂and/or CN.

In a fourteenth embodiment of the first aspect, B may also includepyrimidinyl.

In a fifteenth embodiment of the first aspect, R^(b) as part of D mayalso include SO₂C₁₋₆alkyl, acetyl, and phenyl optionally substitutedwith 1-3C₁₋₆alkyl; and further wherein the ring as part of R^(z) canalso include spirocyclic tetrahydrofuranyl. In addition, D may alsoinclude

wherein R^(h), Ri=H, OH, or taken together to form C═O, C═N—OH, orC═N—OC₁₋₆alkyl.

In a second aspect, the present disclosure provides a pharmaceuticalcomposition for the treatment of disorders responsive to the reductionof β-amyloid peptide production comprising a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt thereof, in association with a pharmaceutically acceptable carrieror diluent.

In a third aspect, the present disclosure provides a method for thetreatment of disorders responsive to the reduction of β-amyloid peptideproduction in a mammal in need thereof, which comprises administering tosaid mammal a therapeutically effective amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof. In a firstembodiment of the first aspect said disorder is selected fromAlzheimer's Disease (AD), Down Syndrome, mild cognitive impairment(MCI), cerebral amyloid angiopathy (CAA), dementia with Lewy bodies(DLB), amyotrophic lateral sclerosis (ALS-D), inclusion body myositis(IBM), age-related macular degeneration, and cancer. In a secondembodiment of the third aspect, said disorder is selected fromAlzheimer's Disease and Down Syndrome. In a third embodiment of thethird aspect, said disorder is Alzheimer's Disease.

Other aspects of the present disclosure may include suitablecombinations of embodiments disclosed herein.

Yet other aspects and embodiments may be found in the descriptionprovided herein.

The description of the present disclosure herein should be construed incongruity with the laws and principals of chemical bonding. In someinstances it may be necessary to remove a hydrogen atom in orderaccommodate a substituent at any given location.

It should be understood that the compounds encompassed by the presentdisclosure are those that are suitably stable for use as pharmaceuticalagent.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule.

All patents, patent applications, and literature references cited in thespecification are herein incorporated by reference in their entirety. Inthe case of inconsistencies, the present disclosure, includingdefinitions, will prevail.

In some instances, the number of carbon atoms in any particular group isdenoted before the recitation of the group. For example, the term“haloC₁₋₆alkoxy” denotes a haloalkoxy group containing one to six carbonatoms and the term “C₁₋₄alkoxyC₁₋₂alkyl” denotes an alkoxy groupcontaining one to four alkoxy groups attached to the parent molecularmoiety through an alkyl group of one or two carbon atoms. Where thesedesignations exist they supersede all other definitions containedherein.

As used herein, the singular forms “a”, “an”, and “the” include pluralreference unless the context clearly dictates otherwise.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom.

The term “alkoxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three alkoxy groups.

The term “alkoxyalkylcarbonyl,” as used herein, refers to an alkoxyalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkyl,” as used herein, refers to a group derived from astraight or branched chain saturated hydrocarbon containing from one toten carbon atoms.

The term “alkylamino,” as used herein, refers to —NHR^(x), wherein R^(x)is an alkyl group.

The term “alkylaminoalkoxy,” as used herein, refers to an alkylaminogroup attached to the parent molecular moiety through an alkoxy group.

The term “alkylcarbonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “alkylsulfonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfonyl group.

The term “alkylsulfonylamido,” as used herein refers to—C(O)NHS(O)₂R^(x) wherein R^(x) is an alkyl group.

The term “amino,” as used herein, refers to —NH₂.

The term “carbonyl,” as used herein, refers to —C(O)—.

The term “cyano,” as used herein, refers to —CN.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclichydrocarbon ring system having three to fourteen carbon atoms and zeroheteroatoms.

The term “(cycloalkyl)alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three cycloalkyl groups.

The term “cycloalkylamino,” as used herein, refers to —NHR^(x) whereinR^(x) is a cycloalkyl group.

The term “cycloalkylcarbonyl,” as used herein, refers to a cycloalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “cycloalkylsulfonyl,” as used herein, refers to a cycloalkylgroup attached to the parent molecular moiety through a sulfonyl group.

The term “dialkylamino,” as used herein, refers to —NR^(x)R^(y), whereinR^(x) and R^(y) are each alkyl groups.

The term “dialkylaminoalkoxy,” as used herein, refers to a dialkylaminogroup attached to the parent molecular moiety through an alkoxy group.

The term “dialkylaminoalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three dialkylamino groups.

The term “dialkylaminoalkylcarbonyl,” as used herein, refers to adialkylaminoalkyl group attached to the parent molecular moiety througha carbonyl group.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, andI.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, three, or four halogen atoms.

The term “hydroxy,” as used herein, refers to —OH.

The term “hydroxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three hydroxy groups.

The term “methylamino,” as used herein, refers to —NHCH₃.

The term “oxo,” as used herein, refers to ═O.

The term “sulfonyl,” as used herein, refers to —SO₂—.

It should be understood that the disclosure encompasses allstereochemical forms, or mixtures thereof, which possess the ability toreduce β-amyloid peptide production.

Certain compounds of the present disclosure may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present disclosure includes eachconformational isomer of these compounds and mixtures thereof.

The present disclosure is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds may have a variety of potential uses,for example as standards and reagents in determining biologicalactivity. In the case of stable isotopes, such compounds may have thepotential to favorably modify biological, pharmacological, orpharmacokinetic properties.

Certain compounds of the present disclosure may exist in zwitterionicform and the present disclosure includes each zwitterionic form of thesecompounds and mixtures thereof.

The compounds of the present disclosure can exist as pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salt,” as usedherein, represents salts or zwitterionic forms of the compounds of thepresent disclosure which are water or oil-soluble or dispersible, whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of patients without excessive toxicity,irritation, allergic response, or other problem or complicationcommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use. The salts can be prepared during the final isolationand purification of the compounds or separately by reacting a suitablenitrogen atom with a suitable acid. Representative acid addition saltsinclude acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate;digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,formate, fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate,3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate, and undecanoate. Examples of acids which can beemployed to form pharmaceutically acceptable addition salts includeinorganic acids such as hydrochloric, hydrobromic, sulfuric, andphosphoric, and organic acids such as oxalic, maleic, succinic, andcitric.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine The cations of pharmaceutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,and N,N′-dibenzylethylenediamine Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, and piperazine.

When it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as pharmaceuticallyacceptable salts thereof, may be administered as the raw chemical, it ispossible to present the active ingredient as a pharmaceuticalcomposition. Accordingly, the disclosure further provides pharmaceuticalcompositions, which include therapeutically effective amounts ofcompounds of formula (I) or pharmaceutically acceptable salts thereof,and one or more pharmaceutically acceptable carriers, diluents, orexcipients. The compounds of formula (I) and pharmaceutically acceptablesalts thereof, are as described above. The carrier(s), diluent(s), orexcipient(s) must be acceptable in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof. In accordance with another aspect of the disclosurethere is also provided a process for the preparation of a pharmaceuticalformulation including admixing a compound of formula (I), or apharmaceutically acceptable salt thereof, with one or morepharmaceutically acceptable carriers, diluents, or excipients.

The dosage of the compounds of Formula Ito achieve a therapeutic effectwill depend not only on such factors as the age, weight and sex of thepatient and mode of administration, but also on the degree of (3-APreduction desired and the potency of the particular compound beingutilized for the particular disorder of disease concerned. It is alsocontemplated that the treatment and dosage of the particular compoundmay be administered in unit dosage form and that the unit dosage formwould be adjusted accordingly by one skilled in the art to reflect therelative level of activity. The decision as to the particular dosage tobe employed (and the number of times to be administered per day) iswithin the discretion of the physician, and may be varied by titrationof the dosage to the particular circumstances of this invention toproduce the desired therapeutic effect.

A suitable dose of a compound of Formula I or pharmaceutical compositionthereof for a mammal, including man, suffering from, or likely to sufferfrom any condition related to β-AP production as described herein,generally the daily dose will be from about 0.05 mg/kg to about 10 mg/kgand preferably, about 0.1 to 2 mg/kg when administered parenterally. Fororal administration, the dose may be in the range from about 0.1 toabout 75 mg/kg and preferably from 0.1 to 10 mg/kg body weight. Theactive ingredient will preferably be administered in equal doses fromone to four times a day. However, usually a small dosage isadministered, and the dosage is gradually increased until the optimaldosage for the host under treatment is determined In accordance withgood clinical practice, it is preferred to administer the instantcompounds at a concentration level that will produce an effectiveanti-amyloid effect without causing any harmful or untoward sideeffects. However, it will be understood that the amount of the compoundactually administered will be determined by a physician, in the light ofthe relevant circumstances including the condition to be treated, thechoice of compound of be administered, the chosen route ofadministration, the age, weight, and response of the individual patient,and the severity of the patient's symptoms.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intracutaneous, intramuscular, intra-articular, intrasynovial,intrasternal, intrathecal, intralesional, intravenous, or intradermalinjections or infusions) route. Such formulations may be prepared by anymethod known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilemulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing, and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate, or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate, or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, and the like. Lubricantsused in these dosage forms include sodium oleate, sodium chloride, andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, betonite, xanthan gum, and the like. Tablets areformulated, for example, by preparing a powder mixture, granulating orslugging, adding a lubricant and disintegrant, and pressing intotablets. A powder mixture is prepared by mixing the compound, suitablecomminuted, with a diluent or base as described above, and optionally,with a binder such as carboxymethylcellulose, an aliginate, gelating, orpolyvinyl pyrrolidone, a solution retardant such as paraffin, aresorption accelerator such as a quaternary salt and/or and absorptionagent such as betonite, kaolin, or dicalcium phosphate. The powdermixture can be granulated by wetting with a binder such as syrup, starchpaste, acadia mucilage, or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc, ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present disclosure can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material, and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylenesorbitol ethers, preservatives, flavor additive such as peppermint oilor natural sweeteners, or saccharin or other artificial sweeteners, andthe like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds of formula (I), and pharmaceutically acceptable saltsthereof, can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesicles,and multilamellar vesicles. Liposomes can be formed from a variety ofphopholipids, such as cholesterol, stearylamine, or phophatidylcholines.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a course powder which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or nasal drops, include aqueous or oilsolutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and soutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

The present disclosure will now be described in connection with certainembodiments which are not intended to limit its scope. On the contrary,the present disclosure covers all alternatives, modifications, andequivalents as can be included within the scope of the claims. Thus, thefollowing examples, which include specific embodiments, will illustrateone practice of the present disclosure, it being understood that theexamples are for the purposes of illustration of certain embodiments andare presented to provide what is believed to be the most useful andreadily understood description of its procedures and conceptual aspects.

The compounds of the present application can be synthesized using themethods described below, together with synthetic methods known in theart of synthetic organic chemistry, or variations thereon as appreciatedby those skilled in the art. Preferred methods include, but are notlimited to, those described below. All references cited herein arehereby incorporated in their entirety herein by reference.

The compounds may be prepared using the reactions and techniquesdescribed in this section. The reactions are performed in solventsappropriate to the reagents and materials employed and are suitable forthe transformations being effected. Also, in the description of thesynthetic methods described below, it is to be understood that allproposed reaction conditions, including choice of solvent, reactionatmosphere, reaction temperature, duration of the experiment and workupprocedures, are chosen to be the conditions standard for that reaction,which should be readily recognized by one skilled in the art. It isunderstood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reactions proposed. Such restrictionsto the substituents which are compatible with the reaction conditionswill be readily apparent to one skilled in the art and alternate methodsmust then be used.

The starting materials useful to synthesize the compounds of the presentdisclosure are known to those skilled in the art and can be readilymanufactured or are commercially available.

The following methods set forth below are provided for illustrativepurposes and are not intended to limit the scope of the claims. It willbe recognized that it may be necessary to prepare such a compound inwhich a functional group is protected using a conventional protectinggroup then to remove the protecting group to provide a compound of thepresent disclosure. The details concerning the use of protecting groupsin accordance with the present disclosure are known to those skilled inthe art.

The abbreviations used in the present application, includingparticularly in the illustrative schemes and examples which follow, arewell-known to those skilled in the art. Some of the abbreviations usedare as follows:

Chemical abbreviations used in the specification and Examples aredefined as follows: “dba” for dibenzylideneacetone; “t-Bu” fortert-butyl; “DCM” for dichloromethane; “LDA” for lithiumdiisopropylamide; “Ph” for phenyl; “TFA” for trifluoracetic acid; “Et”for ethyl; “DMF” for N,N-dimethylformamide; “OAc” for acetate; “h” forhours, “min” for minutes; and “THF” for tetrahydrofuran.

Examples of methods useful for the production of compounds of thisdisclosure are illustrated in Schemes 1-24. Schemes 1-3 outlinedifferent routes for the synthesis of substituted aniline fragments usedin the preparation of the title compounds. As illustrated in Scheme 1, avariety of substituted heterocycles 1, including but not limited to1H-imidazole, 4-methyl-1H-imidazole, 4-chloro-1H-imidazole,4-(difluoromethyl)-1H-imidazole can be added to substituted chloro- orfluoronitroarenes 2, including but not limited to2-chloro-4-nitroanisole, under basic conditions to provide heteroarylsubstituted nitroarenes 3. Reduction of the compounds 3 using reagentsincluding iron in acidic medium or catalytic hydrogenation, employingcatalysts such as palladium on carbon or other catalysts known to oneskilled in the art, affords substituted anilines 4. While Scheme 1illustrates the preparation of 4-(1H-imidazol-1-yl)anilines 4, it shouldbe recognized to one skilled in the art that this method is widelyapplicable to the synthesis of other 4-heteroarylanilines, including butnot limited to variously substituted 4-(1H-1,2,4-triazol-1-yl)anilinesand 4-(1H-1,2,3-triazol-1-yl)anilines. In addition, substitutednitropyridines can be used in place of the nitroarenes of formula 2 toultimately provide amino-substituted pyridines.

Additional procedures for creating substituted anilines rely on thepalladium-catalyzed coupling of aryl halides or heteroaryl halides toboronic acids (the Suzuki coupling reaction). As shown in Scheme 2,biaryl anilines 10 and 11, and their nitro precursors 8 and 9, can becreated by the coupling of an aryl or heteroaryl boronic esters 5 and 7,respectively, to substituted aryl halides 6, including1-bromo-2-methoxy-4-nitrobenzene. Alternatively, the coupling partnerscan be reversed as is shown in Scheme 3, where coupling of an arylhalide 12 or heteroaryl halide 14 to the boronic ester of the nitroarene 13 creates the substituted nitro arenes 8 and 9, respectively.

These general reaction schemes are intended as illustrations of ageneral reaction process that is highly tolerant of a variety offunctional groups, and these processes are not limited by the specificstructures shown in Schemes 2 and 3. Those skilled in the art will alsorecognize that similar processes including the Stille coupling of arylor heteroaryl halides and aryl or heteroaryl stannanes are alsoexcellent processes to prepare the necessary anilines or their nitroprecursors.

The following schemes outline different routes for the synthesis of2,4-dichloro-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines used in thepreparation of the title compounds. As illustrated on Scheme 4,cyclopentanone 15 can react with a variety of arylmagnesium halides toproduce tertiary alcohols 16. In the presence of dehydrating agents,such as mineral acids or thionyl chloride, these tertiary alcohols canundergo elimination of water to yield olefins 17. Upon treatment withperoxidizing agents, such as performic acid, olefins 17 can betransformed to 2-arylcyclopentanones 18. Abu Thaher, B.; Koch, P.; DelAmo, V.; Knochel, P.; Laufer, S. Synthesis 2008, 2, 225-228.

Alternatively, as indicated in Scheme 5,2-arylcyclopentanones 18 can beprepared by treatment of cyclopenteneoxide 19 with various arylmagnesiumhalides, in the presence of copper salts, such as copper iodide,followed by oxidation of resulting alcohols 20. The said oxidation canbe carried out by a number of oxidation agents known to those skilled inthe arts, with superior results achieved by the use of Dess-Martinperiodinane. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,4155-4156.

Additional ketones useful in the preparation of compounds of claim 1 canbe prepared using the method described in 0. Dirat et al, TetrahedronLetters, 2006,47, 1295. This method, described in Scheme 6, relies onalpha-arylation (Fox et al, Journal of the American Chemical Society,2000, 122, 1360) of available ketones 21 that incorporate acetals orketals at the 4-position. The corresponding ketone starting materials 21are available commercially or can easily be prepared by those skilled inthe art, and a variety of acetals can be used, including the shownethylene glycol ketal or ketals of other alcohols including1,3-propanediol, methanol, ethanol, and others. This chemistry worksequally well to produce unsubstituted alpha-aryl ketones 24.

Additional alpha-aryl ketones can be prepared using the chemistry shownin Scheme 7, where tetrahydro-4H-pyran-4-one is brominated, typicallyusing bromine in dichloromethane or pyrrolidine hydrotribromide as abrominating agent. The resulting alpha-bromo ketone can then be reactedwith a Grignard reagent, and after migration of the aryl group thedesired alpha-aryl ketone 27 is obtained.

As indicated in Scheme 8,2-arylcyclopentanones 18 can be deprotonatedwith a strong base, such as LDA and treated with alkylcyanoformate togive ketoesters 28, which upon reaction with 2-methyl-2-thiopseudoureaprovide 2-amino-7-aryl-6,7-dihydrocyclopenta[e][1,3]oxazin-4(5H)-ones29. The latter compounds undergo acid-catalyzed hydrolysis to form7-aryl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-diones 30.Larsen, J. S.; Christensen, L.; Ludvig, G.; Jorgensen, P. T.; Pedersen,E. B.; Nielsen, C. J. Chem. Soc., Perkin Trans. 12000, 3035-3038.

Alternatively,7-aryl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-diones 31 areavailable by reaction of 2-arylcyclopentanones 18 withN-(chlorocarbonyl)isocyanate (Scheme 9). Subsequent treatment of7-aryl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-diones 31 withammonia in water, followed by chlorination with phosphorus oxychlorideaffords 2,4-dichloro-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines 33.

In a similar manner to the synthesis described in Scheme 9, additionalketones can be reacted with N-(chlorocarbonyl)isocyanate to provideadditional oxazine diones 35 that can be reacted with ammonia to providethe pyrimidine diones 36 (Scheme 10). Chlorination then provides theintermediate dichlorides 37. In a similar way, this chemistry can beperformed using the ketal-protected ketones produced in Scheme 6 toprepare the corresponding fused dichloropyrimidines (Scheme 11).

Synthesis of 2,4-dichloro-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines33 could also be performed according to the pathway described on Scheme12. 4-Chloro-2,6-dimethoxypyrimidine 40 could be deprotonated with astrong base, such as n-butyllithium or 2,2,6,6-tetramethylpiperidine,and quenched with allyl bromide to give5-allyl-4-chloro-2,6-dimethoxypyrimidine 41. Nencka, R.; Votruba, I.;H{hacek over (r)}ebabecký, H.; Jansa, P.; Tlou{hacek over (s)}t'ová, E.;Horská, K.; Masojidková, M.; Holý, A. J. Med. Chem. 2007, 50, 6016-6023.The latter compound can react with α-styrylborinic acids in the presenceof a palladium catalyst, such as tetrakis(triphenylphosphine)palladium,to provide compounds of formula 42 which can undergo ring closure olefinmetathesis under Grubbs conditions to form2,4-dimethoxy-7-aryl-5H-cyclopenta[d]pyrimidines 43. Grubbs, R. H.Handbook of Metathesis, 2003, First Edition, Wiley-VCH. The double bondin compounds 43 can be reduced to give2,4-dimethoxy-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines 44, whichupon acid-catalyzed hydrolysis, followed by chlorination with phosphorusoxychloride afford intermediates 33.

Additional members of the class of compounds of claim 1 can be preparedas is shown in Scheme 13. Carboxylation of benzonitriles followed bysimple reduction using metal catalysis (Palladium on carbon or similarmethods) provides the substituted beta-amino ester 48. Condensation withan acrylic ester provides intermediate 49, which can be alkylated onnitrogen to either directly provide access to R^(d) substituents, orusing the chemistry shown can be protected with a p-methoxybenzyl groupfor later deprotection and introduction of R^(d). The intermediate 50 isthen cyclized in the presence of base (usually KOt-Bu) to provide thebeta-keto ester 51. Condensation of the beta-keto ester 51 with ureaunder basic conditions provides the pyrimidine dione intermediate 52,which can then be chlorinated under standard conditions to provide thedichloride 53. This dichloride can be converted into compounds of claim1 in the usual way (vide infra).

Additional members of the class of compounds of claim 1 can be preparedas is shown in Scheme 14. Esterification of an amino acid followed byalkylation with ethyl 4-bromobutyrate provides intermediate 56, whichcan be alkylated on nitrogen to either directly provide access to R^(d)substituents, or using the chemistry shown can be protected with ap-methoxybenzyl group for later deprotection and introduction of R^(d).The intermediate 57 is then cyclized in the presence of base (usuallyKOt-Bu) to provide the beta-keto ester 58. Condensation of the beta-ketoester 58 with urea under basic conditions provides the pyrimidine dioneintermediate 59, which can then be chlorinated under standard conditionsto provide the dichloride 60. This dichloride can be converted intocompounds of claim 1 in the usual way (vide infra).

As shown in Scheme 15, the dimethoxybenzyl group used to protect thenitrogen atom on compounds of structure 61 can be deprotected, forinstance by the action of a strong acid (TFA in the presence of anisoleas a cation scavenger) to provide the free amine, which can then befurther derivatized, for instance by acylation, sulfonylation, oralkylation in the usual ways to prepare additional compounds of claim 1.Similarly, amine the positional isomer 64 as shown in Scheme 16participates in identical chemistry to access an additional class ofcompounds of claim 1.

Further analogs can be prepared by the chemistry detailed in Scheme 17.Formation of the ester from commercial hydroxyacids 67 under Fisherconditions is followed by alkylation of the alcohol under silver(I)oxide catalysis. Reduction of the olefin and cyclization gives thebeta-keto ester 71. Formation of the pyrimidine dione with KOt-Bu andurea followed by chlorination with POCl₃ gives the dichloride 73, whichis carried forward to compounds of claim 1 as described in Scheme 22.

Additional analogs can be prepared using the chemistry shown in Scheme18. Reaction of pyrimidine-2,4,6-triol with POCl₃ in DMF provides thechlorinated aldehyde 75. Protection of the aldehyde is followed byreaction with a Grignard reagent to produce the dichloride reagent 77.After hydrolytic deprotection and reduction of the aldehyde to thealcohol, the tetrahydrofuran ring can be closed by the action of leadtetraacetate to provide the substituted dichloride 80 which can then beused according to the methods described below to prepare furthercompounds of claim 1.

2,4-Dichloro-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines 81selectively react with primary and secondary amines to give 2-aminoderivatives 82, which under heating can be coupled with anilines 4 toform title compounds 83. (Scheme 19). The said coupling can be performedeither under acidic conditions (for example, using acetic acid), orunder basic conditions, (for example, using sodium hydride).Alternatively, the coupling can be completed under metal catalysis, withconditions known in the literature, for instance the use of palladiumXantphos catalyst in the presence of a strong base (NaOt-Bu) or Na₂CO₃in an aqueous cosolvent mixture (typically THF/water or dioxane/water).

Additional compounds of claim 1 can be prepared by condensation of theappropriate ketal-containing dichlorides with animes and anilines in themanner already described to prepare intermediates 86 (Scheme 20).Deprotection of the ketal, for instance with aqueous acid produces theketone 88 which is a very useful intermediate for the production offurther compounds. The ketone can be directly condensed with aminesunder reductive conditions (reductive alkylation) to prepare substitutedamine compounds 89. Alternatively, the ketone can be reduced withhydride reagents such as NaBH₄ or LiAlH₄ to provide the alcohol. Thealcohol 90 can be activated, for instance as the methanesulfonate, andthen displaced with nucleophiles including thiols, azide or othernucleophiles. Oxidation of the thiol prepares the sulfoxide and thesulfone. Reduction of the azide produces a facile entry into the amine,which can also be further alkylated to produce additional compounds ofclaim 1.

An additional method for the preparation of analogs of claim 1 isdescribed in Scheme 21. Again starting with the aldehyde 76, addition oflithiated phenyldithiane provides intermediate 92. Deprotection of theprotecting groups provides the keto aldehyde 93, which can be closed tothe substituted pyrrolidine 94 by sequential reductive alkylation. Theamine can either directly introduce a desired R^(d) substituent, or asis described in the scheme an amine that introduces a protecting group(including 4-methoxybenzyl) can be used. According to the methodsherein, the dichloride thus obtained can be transformed into compoundsof claim 1. Additional analogs can then be prepared by deprotection ofthe 4-methoxybenzyl group using methods known to those in the art, suchas TFA with Anisole as a cation scavenger, followed by additionalalkylation, acylation, or sulfonylation using known methods.

In a general way, the additional pyrimidine dichlorides prepared usingthe methods described above, or other methods known in the art can betransformed into additional analogs of claim 1 as demonstrated in Scheme22. Pyrimidine dichlorides are reacted with amines to provide thechlorides 99 which correspond to the structures D-E as described inclaim 1, where the bond that attaches the structure D-E to the ABNHfragment is activated as a displaceable chloride group. The titlecompounds of claim 1 are then prepared by condensing the chlorides 99with the anilines ABNH₂ according to the methods previously described(Scheme 19).

The racemic title compounds can be separated by chiral methods known toa reasonable person skilled in the arts, to provide individualenantiomers (Scheme 23). This is demonstrated below in thecyclopenta[d]pyrimidine series, but equally applies to the other racemiccompounds described herein.

An additional method for producing compounds of claim 1 is demonstratedin Scheme 23. Commercial 4-chloro-2,6-dimethoxypyrimidine 101 can bedeprotonated using either butyllithium or lithium tetramethylpiperididefollowed by allylation to produce the protected pyrimidine 102. Suzukicoupling of phenyl vinyl boronic acid under palladium catalysis providesthe diene 103 which can be efficiently cyclized by ring-closingmetathesis using standard conditions with Grubbs' II catalyst. Theolefin can then be reduced to provide intermediate 105. Deprotection andchlorination under standard conditions provides an additional route tomake dichlorides 106 which can be converted to compounds of claim 1using the chemistry shown in Scheme 22.

The racemic title compounds can be separated by chiral methods known toa reasonable person skilled in the arts, to provide individualenantiomers (Scheme 24). This is demonstrated below in thecyclopenta[d]pyrimidine series, but equally applies to the other racemiccompounds described herein.

“HPLC” is an abbreviation used herein for high pressure liquidchromatography. “LC-MS” refers to high pressure liquid chromatographycarried out according to the definition for HPLC with a massspectrometry detector. HPLC solvent conditions: When described asperformed under “standard conditions”, samples were dissolved inmethanol (1 mg/mL) and run using a gradient program with a solvent flowrate of 1.0 mL/min. Reverse phase preparatory HPLC: When described asperformed under “standard conditions”, samples (approx. 20 mg) weredissolved in methanol (10 mg/mL) and purified on a 30 mm×100 mmWaters-Atlantis S5 column using a 10 minute gradient elution from 0% to100% buffer B in buffer A (buffer A=10% CH₃OH/90% water/0.1% TFA andbuffer B=90% MeOH/10% water/0.1% TFA). at 40 mL/minute.

Proton NMR spectra were obtained on a Bruker 400 or 500 spectrometer.Data were referred to the lock solvent.

The examples provided are intended to assist in a further understandingof the present disclosure. Particular materials employed, species andconditions are intended to further illustrate the specific embodimentsof the invention and not limit the reasonable scope thereof.

Synthesis of Intermediates

Preparation A

4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline

Intermediate A(1)

4-chloro-1-(2-methoxy-4-nitrophenyl)-1H-imidazole

A mixture of 4-chloro-1H-imidazole (5.0 g, 48.8 mmol),1-chloro-2-methoxy-4-nitrobenzene (9.15 g, 48.8 mmol), and potassiumhydroxide flakes (2.74 g, 48.8 mmol) in anhydrous DMSO (50 mL) washeated at 80° C. for 20 h. The reaction mixture was allowed to cool tort and was poured into 800 mL of water with vigorous stirring. Theresulting yellow-orange precipitate was collected by vacuum filtrationusing a coarse sintered glass funnel The crude wet solid was transferredto a 1 L Erlenmeyer flask. Absolute ethanol (250 mL) was added to theflask and the resulting suspension was heated until all of the solidsdissolved. The clear solution was cooled to rt and the desired productslowly crystallized. After 2 h, the crystalline solid was collected byvacuum filtration and rinsed with 100 mL of fresh ethanol. The solid wasdried under high vacuum to afford4-chloro-1-(2-methoxy-4-nitrophenyl)-1H-imidazole (5.2 g, 42% yield) asan off-white crystalline solid. LC-MS (M+H)⁺=254.0. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.94-8.01 (m, 2H) 7.76 (d, J=1.53 Hz, 1H) 7.45 (d, J=8.55Hz, 1H) 7.21 (d, J=1.53 Hz, 1H) 4.02 (s, 3H).

Preparation A 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline

Iron powder-325 mesh (4.6 g, 82 mmol) was added to a 500 mL round bottomflask charged with a mixture of4-chloro-1-(2-methoxy-4-nitrophenyl)-1H-imidazole (5.2 g, 20.5 mmol),absolute ethanol (100 mL), and glacial acetic acid (50 mL). Awater-cooled reflux condenser was attached to the flask and theheterogeneous mixture was heated to 100° C. with vigorous stirring for30 min. The reaction mixture allowed to cool to rt and was added to achilled and stirred solution of 3 M NaOH (291 mL). The resulting mixturewas poured into a separatory funnel and extracted with EtOAc (3×250 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo to afford4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (4.57 g, 97% yield) as asolid. LC-MS (M+H)⁺224.0. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.47 (d, J=1.22Hz, 1H) 7.00 (d, J=8.24 Hz, 1H) 6.99 (d, J=1.53 Hz, 1H) 6.32 (d, J=2.44Hz, 1H) 6.29 (dd, J=8.24, 2.44 Hz, 1H) 3.88 (br. s., 2H) 3.78 (s, 3H).

Preparation AA 4-(4-cyano-1H-imidazol-1-yl)-3-methoxyaniline

Intermediate AA(1)

4-cyano-1-(2-methoxy-4-nitrophenyl)-1H-imidazole

To a solution of 1H-Imidazole-4-carbonitrile (300 mg, 3.22 mmol) and4-Fluoro-3-methoxynitrobenzene (552 mg, 3.22 mmol) in DMF (Volume: 6446μl) was added K2CO3 (891 mg, 6.45 mmol). The resulting mixture wasbrought to 120° C. and stirred overnight. The reaction mixture wasdiluted with EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL),dried over MgSO₄, filtered and concentrated in vacuo to give1-(2-methoxy-4-nitrophenyl)-1H-imidazole-4-carbonitrile (698 mg, 2.86mmol, 89% yield). LC-MS (M+H)⁺=245.0. ¹H NMR (500 MHz, MeOD) δ ppm8.30-8.34 (1H), 8.19-8.23 (1H), 8.09-8.12 (1H), 8.00-8.05 (1H),7.71-7.79 (1H), 4.02-4.10 (3H).

Preparation AA 4-(4-cyano-1H-imidazol-1-yl)-3-methoxyaniline

To a solution of 1-(2-methoxy-4-nitrophenyl)-1H-imidazole-4-carbonitrile(689 mg, 2.82 mmol) in EtOH (Ratio: 2, Volume: 15 mL) was added AceticAcid (Ratio: 1.000, Volume: 7.50 mL) and Iron (630 mg, 11.29 mmol). Theresulting mixture was brought to 100° C. and stirred for 2 h. Thereaction was then diluted with water and brought to pH 8 by the additionof 1 N aqueous sodium hydroxide. This mixture was extracted with EtOAc(3×5 mL). The combined extracts were washed with water (5 mL), brine (5mL), dried over MgSO₄, filtered and concentrated in vacuo. LC-MS(M+H)⁺=215.0.

Preparation B 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline

Intermediate B(1)

1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole

A mixture of 3-methyl-1H-1,2,4-triazole (15.0 g, 181 mmol),1,2-difluoro-4-nitrobenzene (28.7 g, 181 mmol), and sodium bicarbonate(15.2 g, 181 mmol) in DMSO (100 mL) was heated at 80° C. for 48 h. Thereaction mixture was allowed to cool to rt and was poured into water(800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). Thecombined organic extracts were sequentially washed with water (500 mL)and brine solution (100 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude reaction mixturewas purified using silica gel chromatography (30-80% EtOAc/hexane,linear gradient) to afford two regioisomeric products. Pure fractions ofthe less polar regioisomer were combined and concentrated to afford1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (7.2 g, 30.8 mmol,17% yield) as an off-white solid. Pure fractions of the more polarregioisomer were combined and concentrated to afford1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (6.23 g, 28.0mmol, 15% yield) as an off-white solid. Data for1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole: LC-MS(M+H)⁺=223.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.73 (d, J=2.7 Hz, 1H),8.15-8.26 (m, 3H), 2.53 (s, 3H).

Preparation B 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline

10% Palladium on carbon (2.50 g, 23.5 mmol) was added under anatmosphere of nitrogen to a chilled (ice-water bath) solution of1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (15.0 g, 67.5mmol, from preparation A, step 1) dissolved in methanol (400 mL). Theflask was repeatedly evacuated and flushed with hydrogen gas (doubleballoon). The resulting mixture was allowed to warm to rt and left tostir for 72 h under the hydrogen atmosphere. The vessel was subsequentlypurged with nitrogen gas. The reaction vessel and it contents werechilled (ice-water bath) and an additional portion of 10% Palladium oncarbon (2.50 g, 23.5 mmol) was added. The flask was repeatedly evacuatedand flushed with hydrogen gas (double balloon). The resulting mixturewas allowed to warm to rt and left to stir for 6 h under the hydrogenatmosphere. The vessel was subsequently purged with nitrogen gas. Thecrude reaction mixture was filtered through a short plug of diatomaceousearth (Celite®). The reaction vessel and the Celite® were rinsed withfresh methanol. The combined filtrates were concentrated in vacuo. Theresidue was dried under high vacuum overnight to afford3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (12.1 g, 63.0 mmol,93% yield) as a blackish/grey solid. LC-MS (M+H)⁺193.2. ¹H NMR (500 MHz,CDCl₃) δ ppm 8.31 (d, J=2.4 Hz, 1H), 7.47 (t, J=8.7 Hz, 1H), 6.47-6.58(m, 2H), 3.97 (br. s., 2H), 2.48 (s, 3H).

Preparation C 3-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline

Intermediate C(1)

1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole

A mixture of 3-methyl-1H-1,2,4-triazole (15.0 g, 181 mmol),1,2-difluoro-4-nitrobenzene (28.7 g, 181 mmol), and sodium bicarbonate(15.2 g, 181 mmol) in DMSO (100 mL) was heated at 80° C. for 48 h. Thereaction mixture was allowed to cool to rt and was poured into water(800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). Thecombined organic extracts were sequentially washed with water (500 mL)and brine solution (100 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude reaction mixturewas purified using silica gel chromatography (30-80% EtOAc/hexane,linear gradient) to afford two regioisomeric products. Pure fractions ofthe less polar regioisomer were combined and concentrated to afford1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (7.2 g, 30.8 mmol,17% yield) as an off-white solid. Pure fractions of the more polarregioisomer were combined and concentrated to afford1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (6.23 g, 28.0mmol, 15% yield) as an off-white solid. Data for1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole: LC-MS(M+H)⁺=223.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.18-8.24 (m, 2H) 8.04 (s,1H) 7.69-7.78 (m, 1H) 2.47-2.53 (m, 3H).

Preparation C 3-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline

10% Palladium on carbon (1.5 g, 14.1 mmol) was added under an atmosphereof nitrogen to a chilled (ice-water bath) solution of1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (3.7 g, 17 mmol)dissolved in methanol (200 mL). The flask was repeatedly evacuated andflushed with hydrogen gas (double balloon). The resulting mixture wasallowed to warm to rt and left to stir for 18 h under the hydrogenatmosphere. The vessel was subsequently purged with nitrogen gas. Thecrude reaction mixture was filtered through a short plug of diatomaceousearth (Celite®). The reaction vessel and Celite® were rinsed with freshmethanol. The combined filtrates were concentrated in vacuo. The residuewas dried under high vacuum to afford3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (3.14 g, 91% yield)as a blackish/grey solid. LC-MS (M+H)⁺193.1. ¹H NMR (500 MHz, CDCl₃) δppm 7.91 (s, 1H) 7.14 (t, J=8.55 Hz, 1H) 6.43-6.53 (m, 2H) 4.04 (br. s.,2H) 2.36 (s, 3H).

Preparation D 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline

Intermediate D(1)

1-(2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole

A mixture of 3-methyl-1H-1,2,4-triazole (5.0 g, 60.2 mmol),1-chloro-2-methoxy-4-nitrobenzene (11.3 g, 60.2 mmol), and KOH flakes(3.4 g, 48.1 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 6h. The reaction mixture was allowed to cool to rt and was poured into800 mL of water with vigorous stirring. The aqueous mixture wasextracted with EtOAc (3×200 mL). The combined organics were washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified using silica gel chromatography (0-2%MeOH/chloroform, linear gradient) to afford1-(2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (3.7 g, 26%yield). LC-MS (M+H)⁺+235.2.

Preparation D 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline

10% Palladium on carbon (1.2 g) was added under an atmosphere ofnitrogen to a chilled (ice-water bath) solution of1-(2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (3.7 g, 12.7mmol) dissolved in methanol (250 mL). The flask was repeated evacuatedand flushed with hydrogen gas (double balloon). The resulting mixturewas allowed to warm to rt and left to stir for 18 h under the hydrogenatmosphere. Purged with nitrogen gas. Filtered the crude reactionmixture through a short diatomaceous earth (Celite®) plug. Rinsedreaction vessel and plug with methanol. Concentrated filtrate in vacuo.Dried residue on high vacuum overnight to afford3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (2.44 g, 94% yield)as a reddish solid. LC-MS (M+H)⁺205.2. ¹H NMR (500 MHz, CDCl₃) δ ppm8.35 (s, 1H) 7.36 (d, J=8.55 Hz, 1H) 6.29-6.34 (m, 2H) 3.80 (s, 3H) 2.46(s, 3H).

Preparation Dd 3-methoxy-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline

Intermediate C(1) was reacted with NaOMe in DMF to afford1-(2-methoxy-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole, which wasreduced with Fe and ammonium chloride to afford the title compound.LC-MS (M+H)⁺205.1. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.90 (1H, s),7.05 (1H, d, J=7.93 Hz), 6.27-6.34 (2H, m), 3.91 (2H, br. s.), 3.73 (3H,s), 2.29 (3H, s).

Preparation E 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline

Intermediate E(1)

1-(2-methoxy-4-nitrophenyl)-4-methyl-1H-imidazole

A mixture of 4-methyl-1H-imidazole (18.0 g, 53.5 mmol),1-chloro-2-methoxy-4-nitrobenzene (10.0 g, 53.5 mmol), and potassiumhydroxide (4.5 g, 80.3 mmol) in DMSO (50 mL) was heated at 110° C. for24 h. The reaction mixture was allowed to cool to rt and was poured into1000 mL of water. The aqueous mixture was extracted with dichloromethane(3×250 mL). The combined organic extracts were washed with brine, driedover sodium sulfate, filtered, and concentrated in vacuo. The crudereaction mixture was purified using silica gel chromatography (330 gsilica cartridge, 0-2% MeOH/chloroform, linear gradient over 72 min,flow 25 mL/min) to afford1-(2-methoxy-4-nitrophenyl)-4-methyl-1H-imidazole (2.56 g, 20% yield) asa yellow/orange solid. LC-MS (M+H)⁺=234.1. ¹H NMR (500 MHz, CDCl₃) δ ppm7.97-8.00 (m, 1H) 7.93-7.97 (m, 2H) 7.45 (d, J=8.85 Hz, 1H) 7.02 (s, 1H)4.02 (s, 3H) 2.35 (s, 3H).

Preparation E 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline

10% Palladium on carbon (250 mg) was added under an atmosphere ofnitrogen to a chilled (ice-water bath) solution of1-(2-methoxy-4-nitrophenyl)-4-methyl-1H-imidazole (2.56 g, 11.0 mmol)dissolved in methanol (150 mL). The flask was repeated evacuated andflushed with hydrogen gas (double balloon). The resulting mixture wasallowed to warm to rt and left to stir for 18 h under the hydrogenatmosphere. Purged with nitrogen gas. Filtered the crude reactionmixture through a short diatomaceous earth (Celite®) plug. Rinsedreaction vessel and plug with methanol. Concentrated filtrate in vacuo.Dried residue on high vacuum overnight to afford3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (2.25 g, 100% yield) as ablackish/grey waxy solid. LC-MS (M+H)⁺204.1. ¹H NMR (500 MHz, CDCl₃) δppm 7.69 (s, 1H) 7.01 (d, J=8.55 Hz, 1 H) 6.82 (s, 1H) 6.33 (d, J=2.14Hz, 1H) 6.30 (d, J=8.55 Hz, 1H) 3.78 (s, 3H) 2.33 (s, 3H).

Preparation Ee 3-methoxy-4-(4-difluoromethyl-1H-imidazol-1-yl)aniline

Intermediate EE(1)

4-(difluoromethyl)-1H-imidazole

A solution of 1-trityl-1H-imidazole-4-carbaldehyde in dichloromethane at0° C. was added deoxyfluor and stirred for 3 days. The product was thentreated with 1:5 AcOH/HCl at ambient temperature overnight to afford4-(difluoromethyl)-1H-imidazole.

Preparation Ee 3-methoxy-4-(4-difluoromethyl-1H-imidazol-1-yl)aniline

Intermediate EE(1) was reacted as described for Preparation E to affordthe desired Preparation EE. LC-MS (M+H)⁺240.2. ¹H NMR (400 MHz, DMSO-d6)δ ppm 8.42 (s, 1H) 7.93 (s, 1H), 7.48 (d, J=8.4 Hz, 1H) 7.19-6.88 (m,3H) 3.81 (s, 3H).

Preparation F 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline

Intermediate F(1)

2-(3-chloro-1H-1,2,4-triazol-1-yl)-5-nitrophenol

A mixture of 3-chloro-1H-1,2,4-triazole (2.76 g, 26.7 mmol),1-chloro-2-methoxy-4-nitrobenzene (5.0 g, 26.7 mmol), potassiumhydroxide flakes (1.496 g, 26.7 mmol), and DMSO (25 mL) was heated in asealed reaction vessel 100° C. for 24 h. The reaction was allowed tocool to rt and additional portions of 3-chloro-1H-1,2,4-triazole (1.38g, 0.5 equiv) and potassium hydroxide (0.75 g, 0.5 equiv) were added.The reaction vessel was resealed and heated to 110° C. for an additional24 h. The resulting mixture was allowed to cool to rt and was pouredinto 500 mL of water. The aqueous mixture was extracted with EtOAc(3×100 mL). The combined organics were washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified using silica gel chromatography (0-5% MeOH/chloroform, lineargradient over 144 min, flow 25 mL/min) to afford2-(3-chloro-1H-1,2,4-triazol-1-yl)-5-nitrophenol (0.924 g, 3.84 mmol,14.4% yield). LC-MS (M+H)⁺=241.0. ¹H NMR (500 MHz, CDCl₃) δ ppm 11.97(br. s., 1H) 9.24 (s, 1H) 7.90-7.95 (m, 1H) 7.89 (d, J=2.44 Hz, 1 H)7.84 (dd, J=8.85, 2.44 Hz, 1H).

Intermediate F(2)

3-chloro-1-(2-methoxy-4-nitrophenyl)-1H-1,2,4-triazole

Iodomethane (0.860 mL, 13.82 mmol) was added to a mixture of2-(3-chloro-1H-1,2,4-triazol-1-yl)-5-nitrophenol (1.33 g, 5.53 mmol),potassium hydroxide (0.388 g, 6.91 mmol), and DMSO (25 mL). The mixturewas left to stir at rt for 24 h. The reaction mixture was poured intowater (250 mL) and extracted with EtOAc (3×100 mL). The combinedextracts were washed with water, washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The crude residue waspurified using silica gel column chromatography (0-1% MeOH/chloroform,linear gradient over 72 min, flow 25 mL/min). The pure fractions werecombined and concentrated to afford3-chloro-1-(2-methoxy-4-nitrophenyl)-1H-1,2,4-triazole (0.924 g, 3.63mmol, 65.6% yield) as a light yellow solid. LC-MS (M+H)⁺=255.0. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.35 (s, 1H) 7.36 (d, J=8.55 Hz, 1H) 6.29-6.34(m, 2H) 3.80 (s, 3H) 2.46 (s, 3H).

Preparation F 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline

Water (8 mL) and dioxane (8 mL) were added to a mixture of3-chloro-1-(2-methoxy-4-nitrophenyl)-1H-1,2,4-triazole (0.900 g, 3.53mmol) and sodium sulfide (1.379 g, 17.67 mmol) in a 20 mL vial. The vialwas capped and heated at 70-80° C. for 24 hours. The mixture was cooledto rt, poured into water (300 mL) and extracted with EtOAc (2×150 mL).The combined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated in vacuo to afford4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (577 mg, 73%) as abrown solid. LC-MS (M+H)⁺225.1.

Preparation FF

6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine

Intermediate FF(1)

2-(4-chloro-1H-imidazol-1-yl)-3-methoxy-5-nitropyridine

A mixture of 4-chloro-1H-imidazole (2.72 g, 26.5 mmol),2-chloro-3-methoxy-5-nitropyridine (5.0 g, 26.5 mmol), and KOH flakes1.488 g, 26.5 mmol) in anhydrous DMSO (25 mL) was heated at 80° C. for 5h. The reaction mixture was allowed to cool to rt and was poured into1.0 L of water with vigorous stirring. The mixture was stirred at rt for16 h. The precipitate was collected by vacuum filtration using a coarsesintered glass funnel The solid was dried under high vacuum for 24 h toprovide 2-(4-chloro-1H-imidazol-1-yl)-3-methoxy-5-nitropyridine (5.22 g,20.50 mmol, 77% yield) as a light brown solid. LC-MS (M+H)⁺=255.0. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.94 (d, J=2.44 Hz, 1H) 8.51 (d, J=1.83 Hz,1H) 8.42 (d, J=2.44 Hz, 1H) 8.02 (d, J=1.83 Hz, 1 H) 4.12 (s, 3H).

Preparation FF 6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine

Iron powder-325 mesh (2.19 g, 39.3 mmol) was added to a flask chargedwith a mixture of2-(4-chloro-1H-imidazol-1-yl)-3-methoxy-5-nitropyridine (5.0 g, 19.64mmol), absolute ethanol (50 mL), and glacial acetic acid (20 mL). Awater-cooled reflux condenser was attached to the flask and theheterogeneous mixture was heated to 100° C. with vigorous stirring for30 min. The reaction mixture was allowed to cool to rt and wasneutralized upon addition to a chilled and vigorously stirred solutionof 5 M NaOH. The resulting mixture was poured into a separatory funneland extracted with EtOAc. The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo to afford6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (3.12 g, 71%yield). LC-MS (M+H)⁺225.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.06 (d, J=1.83Hz, 1 H) 7.53 (dd, J=13.28, 1.98 Hz, 2H) 6.70 (d, J=2.44 Hz, 1H) 3.90(s, 3H) 3.86 (br. s., 2H).

Preparation FFF2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline

Intermediate FFF(1)

1-(5-fluoro-2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole

A mixture of 3-methyl-1H-1,2,4-triazole (2.20 g, 26.4 mmol),1,5-difluoro-2-methoxy-4-nitrobenzene (5.00 g, 26.4 mmol), and potassiumcarbonate (3.65 g, 26.4 mmol) in anhydrous DMSO (50 mL) was heated at80° C. for 24 h. The reaction mixture was allowed to cool to rt and waspoured into 500 mL of water/10 mL brine solution. The aqueous mixturewas extracted with EtOAc (2×250 mL). The combined organic extracts werewashed with water (500 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude reaction mixture was purified usingsilica gel column chromatography (50% EtOAc/hexane) to afford1-(5-fluoro-2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.24 g,18% yield). LC-MS (M+H)⁺=253.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.95 (s,1H) 8.00 (d, J=11.60 Hz, 1H) 7.80 (d, J=6.10 Hz, 1H) 4.09 (s, 3H) 2.50(s, 3H).

Preparation FFF2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline

10% Palladium on carbon (0.523 g, 4.92 mmol) was added under anatmosphere of nitrogen to a chilled (ice-water bath) solution of1-(5-fluoro-2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.24 g,4.92 mmol) dissolved in methanol (100 mL). The flask was repeatedlyevacuated and flushed with hydrogen gas (double balloon). The resultingmixture was allowed to warm to rt and left to stir for 18 h under thehydrogen atmosphere. The vessel was subsequently purged with nitrogengas. The crude reaction mixture was filtered through a shortdiatomaceous earth (Celite®) plug. The reaction vessel and plug wererinsed with fresh methanol. The combined filtrates were concentrated invacuo. The residue was dried on high vacuum overnight to afford2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (1.05 g,96% yield) as a gray solid. LC-MS (M+H)⁺223.1. ¹H NMR (500 MHz, CDCl₃) δppm 8.46 (s, 1H) 7.39 (d, J=11.29 Hz, 1H) 6.44 (d, J=7.63 Hz, 1H) 3.89(br. s., 2H) 3.83 (s, 3H) 2.47 (s, 3H).

Preparation G2,4-Dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Intermediate G(1)

Cyclopentenylbenzene

To a solution of 3.0 M solution of phenylmagnesium bromide in ether(49.7 mL, 149 mmol) was added THF (300 mL). To this solution cooled to0° C. cyclopentanone (13.23 mL, 149 mmol) was added. The reactionmixture was stirred at room temperature for 30 min, then—at reflux for 2h. Ice (20 g) was added, followed by 6N HCl, until the precipitatedissolved. The product was extracted with ether. The combined etheriallayers were washed with saturated sodium bicarbonate solution, driedover anhydrous magnesium sulfate and filtered. The solvent was removedin vacuum and the residue was purified by column chromatography onsilica gel to give cyclopentenylbenzene (21.49 g, 149 mmol, 100% yield)as colorless oil. LC-MS (M+H)⁺=145.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.48(2H, d, J=7.3 Hz), 7.35 (2H, t, J=7.8 Hz), 7.22-7.27 (1H, m), 6.22 (1H,t, J=2.1 Hz), 2.70-2.80 (2H, m), 2.52-2.64 (2H, m), 2.01-2.12 (2H, m).

Intermediate G(2)

2-Phenylcyclopentanone

A mixture of 30% hydrogen peroxide (23 mL, 149 mmol) and 85% formic acid(100 mL, 2619 mmol) was heated at 40° C. for 15 minutes. The mixture wascarefully added to cyclopentenylbenzene (21.49 g, 149 mmol) and theresulting two-phase system was vigorously stirred at room temperaturefor 4 h. An exothermic reaction was observed in the beginning. In theend of the stirring the solution became homogeneous. The reactionmixture was carefully quenched with saturated aqueous solution of sodiumbicarbonate. The product was extracted with ether. The combined etheriallayers were dried over anhydrous magnesium sulfate and filtered. Thesolvent was removed in vacuum and the product was purified by columnchromatography on silica gel to give 2-phenylcyclopentanone (19.995 g,125 mmol, 84% yield) as brown oil. LC-MS (M+H)⁺=161.0. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.38 (1H, t, J=7.3 Hz), 7.30-7.35 (2H, m), 7.19 (2H, d,J=7.3 Hz), 3.28-3.37 (1H, m), 2.71 (1H, td, J=4.6, 2.7 Hz), 2.58-2.63(1H, m), 2.43-2.55 (1H, m), 2.29 (1H, ddd, J=19.0, 10.5, 9.0 Hz),2.07-2.21 (1H, m), 1.88-1.99 (1H, m).

Intermediate G(3)

Ethyl 2-oxo-3-phenylcyclopentanecarboxylate

To a solution of diisopropylamine (6.62 mL, 46.8 mmol) in THF (200 mL)at −78° C. was added a 1.6 M solution of n-butyllithium in hexanes (29.3mL, 46.8 mmol). The solution was stirred for 30 min at −78° C. andtreated with a solution of 2-phenylcyclopentanone (5 g, 31.2 mmol) in 50mL of dry THF. After stirring for 30 min at −78° C., ethylcarbonocyanidate (3.36 mL, 34.3 mmol) was added to the reaction mixture.The resulting solution was warmed to 25° C. with stirring over 3 h. Thereaction mixture was quenched with 10 mL of water, washed with brine,dried over anhydrous sodium sulfate, concentrated in vacuum, andpurified by column chromatography on silica gel to afford ethyl2-oxo-3-phenylcyclopentanecarboxylate (5.3 g, 22.82 mmol, 73% yield) ascolorless oil. LC-MS (M+K)⁺=273.2. ¹H NMR (500 MHz, CDCl₃) δ ppm7.32-7.39 (2H, m), 7.25-7.31 (1H, m), 7.19-7.25 (2H, m), 4.18-4.32 (2H,m), 3.29-3.55 (2H, m), 1.87-2.62 (4H, m), 1.28-1.39 (3H, m).

Intermediate G(4)

2-Amino-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazin-4(5H)-one

2-Methyl-2-thiopseudourea sulfate (1.336 g, 9.61 mmol) was dissolved inwater (10 mL) and KOH (1.128 g, 20.10 mmol) was added. Under stirring,ethyl 2-oxo-3-phenylcyclopentanecarboxylate (2.03 g, 8.74 mmol) wasadded and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was filtered, washed with water andether, and dried over anhydrous sodium sulfate to afford2-amino-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazin-4(5H)-one (1.22 g,5.35 mmol, 61.2% yield) as white solid. LC-MS (M+H)⁺=229.1. ¹H NMR (500MHz, dimethylsulfoxide-d6) δ ppm 7.57-7.85 (2H, m), 7.08-7.47 (5H, m),4.25-4.38 (1H, m), 1.72-2.73 (3H, m), 1.09-1.31 (1H, m).

Intermediate G(5)

7-Phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione

2-Amino-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazin-4(5H)-one (900 mg,3.94 mmol) was dissolved in a 3M aqueous hydrogen chloride solution (32mL, 96 mmol) under stirring. The mixture was heated at reflux for 1 h.The reaction mixture was cooled and extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution and brine, dried over anhydrous sodium sulfate, concentrated invacuum and purified by column chromatography on silica gel to afford7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (350 mg,1.527 mmol, 38.7% yield). LC-MS (M+H)⁺=230.0. ¹H NMR (500 MHz, CDCl₃) δppm 8.34 (1H, br s), 7.35 (2H, t, J=7.3 Hz), 7.27-7.32 (1H, m), 7.18(2H, d, J=7.3 Hz), 4.20 (1H, t, J=7.6 Hz), 2.82-2.91 (1H, m), 2.61-2.79(2H, m), 2.11-2.21 (1H, m).

-   -   or

A solution of 2-phenylcyclopentanone (19.995 g, 125 mmol) andN-(chlorocarbonyl)isocyanate (23.70 g, 225 mmol) was stirred at 58° C.for 1 h and at 130° C. for 45 min. The resulting tarrified reactionmixture was dissolved in ethyl acetate and neutralized with saturatedaqueous sodium bicarbonate solution. The organic layer was dried overanhydrous magnesium sulfate and filtered. The product was purified bycolumn chromatography on silica gel to give7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (3.751 g,16.36 mmol, 13% yield) as brownish solid. LC-MS (M+H)⁺=230.0. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.34 (1H, br s), 7.35 (2H, t, J=7.3 Hz),7.27-7.32 (1H, m), 7.18 (2H, d, J=7.3 Hz), 4.20 (1H, t, J=7.6 Hz),2.82-2.91 (1H, m), 2.61-2.79 (2H, m), 2.11-2.21 (1H, m).

Intermediate G(6)

7-Phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

A solution of7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (3.751 g,16.36 mmol) in concentrated ammonia in water (80 mL, 16.36 mmol) washeated in a 350 mL high-pressure flask for 5 h. The solvent was removedin vacuum to give7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (3.73g, 16.34 mmol, 100% yield) as brown solid. LC-MS (M+H)⁺=229.1. ¹H NMR(500 MHz, dimethylsulfoxide-d6) δ ppm 7.34 (2H, t, J=7.5 Hz), 7.26 (1H,t, J=7.3 Hz), 7.18 (2H, d, J=7.3 Hz), 5.39 (1H, br s), 4.14 (1H, d,J=7.3 Hz), 2.43-2.68 (2H, m), 1.80-1.88 (2H, m).

Preparation G2,4-Dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (1.241g, 5.44 mmol) in phosphoryl trichloride (14.93 mL, 163 mmol) was heatedin microwave at 110° C. for 1 h. Once ice melted, the product wasextracted with dichloromethane. The combined organic extracts were driedover anhydrous magnesium sulfate and filtered. The solvent was removedin vacuum and the residue was purified by column chromatography onsilica gel to give2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.132 g,72%) as light brown solid. LC-MS (M+H)⁺=265.0. ¹H NMR (500 MHz, CDCl₃) δppm 7.31-7.37 (2H, m), 7.27 (1H, d, J=7.0 Hz), 7.15 (2H, d, J=7.9 Hz),4.44 (1H, t, J=8.2 Hz), 3.09-3.18 (1H, m), 2.97-3.06 (1H, m), 2.73 (1H,ddd, J=9.0, 4.7, 4.6 Hz), 2.26 (1H, ddd, J=8.5, 7.0, 6.7 Hz).

Preparation Ga

2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation G) (395 mg, 1.49 mmol) in THF (3700 μL), 2 M MeNH₂ in THF(3700 μL, 7.45 mmol) was added. The reaction was allowed to stir at rt.When the reaction was complete, removed solvent and applied residue tosilica gel. Eluted with EtOAc/Hex to afford the desired2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(80.8 mg, 0.220 mmol, 69.1% yield). LC-MS (M+H)⁺=260.1. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.07 (3H, dd, J=8.5, 5.5 Hz), 6.96 (2H, t, J=8.7 Hz), 4.72(1H, br s), 4.23 (1H, t, J=7.2 Hz), 3.09 (3H, d, J=4.9 Hz), 2.67-2.77(1H, m), 2.58-2.67 (2H, m), 2.01-2.11 (1H, m).

Preparation Gb2-Chloro-N,N-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg,0.754 mmol) and excess dimethylamine (3.77 mL, 7.54 mmol) in MeOH (2 mL)was stirred at rt for 1 h. The solvent was removed in vacuum to afford2-chloro-N,N-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(207 mg, 0.756 mmol, 100% yield). LC-MS (M+H)⁺=274.2.

Preparation Gc2-Chloro-N-ethyl-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg,0.566 mmol) and excess N-methylethanamine (0.486 mL, 5.66 mmol) in MeOH(2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum toafford2-chloro-N-ethyl-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(163 mg, 0.566 mmol, 100% yield). LC-MS (M+H)⁺=288.2.

Preparation Gd

4-(Azetidin-1-yl)-2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg,0.566 mmol) and excess azetidine (162 mg, 2.83 mmol) in methanol (1 mL)was stirred at rt for 30 min. The solvent was removed in vacuum toafford4-(azetidin-1-yl)-2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine(162 mg, 0.567 mmol, 100% yield). LC-MS (M+H)⁺=286.3.

Preparation Ge2-Chloro-N-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(350 mg, 1.236 mmol) and trideuteromethylamine hydrochloride

(174 mg, 2.472 mmol) in methanol (3 mL) was added DIPEA (0.432 mL, 2.472mmol). The reaction mixture was stirred at room temperature overnight.The solvent was removed in vacuum and the residue was purified by columnchromatography on silica gel to give2-chloro-N-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amineas brown oil. LC-MS (M+H)⁺=281.2.

Preparation Gf2-chloro-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (170 mg,0.641 mmol) in NMP (2 mL) was added cyclopropanamine (110 mg, 1.924mmol) dropwise. The mixture was stirred at RT for 3 hours. 8 mL of waterwas added to precipitate out the product. The solid was filtered out andair-dried to give a crude2-chloro-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(175 mg, 0.612 mmol, 96% yield), which was used for the next stepwithout any purification. LC-MS (M+H)⁺=286.1

Preparation Gg2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (160 mg,0.60 mmol) in NMP (2 mL) was added cyclobutanamine (129 mg, 1.81 mmol)dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water wasadded to precipitate out the product. The solid was filtered out andair-dried to give a crude2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(177 mg, 0.57 mmol, 94% yield), which was used for the next step withoutany purification. LC-MS (M+H)⁺=300.1

Preparation Gh2-chloro-7-phenyl-N-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (172 mg,0.65 mmol) in NMP (2 mL) was added propan-2-amine (115 mg, 1.95 mmol)dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water wasadded to precipitate out the product. The solid was filtered out,air-dried, and purified via Biotage (12 g, hexanes-70% EtOAc) to give2-chloro-N-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(154 mg, 0.535 mmol, 82% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm 7.30 (2H,t, J=7.5 Hz), 7.20-7.25 (1H, m), 7.15 (1H, d, J=1.5 Hz), 7.13 (1H, s),4.53 (1H, d, J=7.3 Hz), 4.37-4.45 (1H, m), 4.23-4.28 (1H, m), 2.58-2.78(3H, m), 2.10-2.17 (1H, m), 1.27-1.29 (6H, m).

Preparation Gi2-chloro-4-(3-chloroazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

The mixture of 3-chloroazetidine, HCl (217 mg, 1.697 mmol),2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg,0.566 mmol) and DIEA (0.395 mL, 2.263 mmol) in N-Methyl-2-pyrrolidinone(2.0 mL) was stirred at RT for 3 h. Water (8 ml) was added to thereaction mixture. The product precipitated out which was filtered,rinsed with water and air dried. LC-MS (M+H)⁺=320.0. ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 7.21-7.39 (m, 3H) 7.14 (d, J=7.02 Hz, 2H) 4.65-4.84(m, 3H) 4.34-4.48 (m, 2H) 4.23 (dd, J=9.16, 6.41 Hz, 1H) 3.00 (dd,J=8.85, 5.80 Hz, 1H) 2.83-2.93 (m, 1H) 2.54-2.72 (m, 1H) 2.02-2.20 (m,1H).

Preparation Gj2-chloro-4-(3-fluoroazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

3-fluoroazetidine was reacted with Preparation G in the manner ofPreparation Gi to afford the title compound. LC-MS (M+H)⁺=304.1. ¹H NMR(500 MHz, CHLOROFORM-d) δ ppm 7.19-7.37 (m, 3H) 7.15 (d, J=7.32 Hz, 2H)5.39-5.52 (m, 1H) 4.59 (dddd, J=14.88, 10.15, 5.19, 4.88 Hz, 2H)4.30-4.50 (m, 2H) 4.23 (dd, J=9.00, 6.26 Hz, 1H) 2.96-3.07 (m, 1H)2.84-2.96 (m, 1H) 2.56-2.70 (m, 1H) 2.05-2.21 (m, 1H).

Preparation Gk2-chloro-4-(3-methoxyazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

3-methoxyazetidine was reacted with Preparation G in the manner ofPreparation Gi to afford the title compound. LC-MS (M+H)⁺=316.1.

Preparation Gl2-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,8-dioxa-2-azaspiro[3.4]octane

Azetidin-3-one was reacted with Preparation G in the manner ofPreparation Gi to afford1-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one.LC-MS (M+H)⁺=300.0 A mixture of ethylene glycol (119 μL, 2.135 mmol),1-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one(320 mg, 1.068 mmol) and 4-methylbenzenesulfonic acid, H2O (20.31 mg,0.107 mmol) in Benzene (2965 μL) was heated at reflux for 24 h in aDean-stark apparatus. The resulting mixture was concentrated andpurified by Prep-HPLC to afford the title compound. LC-MS (M+H)⁺=344.0.¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.21-7.40 (m, 3H) 7.15 (d, J=7.63Hz, 2H) 4.35-4.53 (m, 4H) 4.23 (dd, J=9.00, 6.26 Hz, 1H) 4.03 (s, 4H)2.96-3.09 (m, 1H) 2.80-2.96 (m, 1H) 2.51-2.70 (m, 1H) 2.03-2.16 (m, 1H).

Preparation Gm2-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octane

5-oxa-2-azaspiro[3.4]octane was reacted with Preparation G in the mannerof Preparation Gi to afford the title compound. LC-MS (M+H)⁺=342.1.

Preparation Gn1-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-one

Pyrrolidin-3-one was reacted with Preparation G in the manner ofPreparation Gi to afford the title compound. LC-MS (M+H)⁺=314.1.

Preparation Go7-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-dioxa-7-azaspiro[4.4]nonane

The mixture of ethylene glycol (46.9 μL, 0.841 mmol),1-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-one(Intermediate Gn) (132 mg, 0.421 mmol) and 4-methylbenzenesulfonic acid,H2O (8.00 mg, 0.042 mmol) in Benzene (1169 μL) was heated at reflux for24 h in a Dean-stark apparatus. The resulting mixture was concentratedand purified by Prep-HPLC (Column: PHENOMENEX LUNA C18 30×100 mm,Solvent A=10 mM Ammonium Acetate in 95:5 H2O/ACN, Solvent B=10 mMAmmonium Acetate in 5:95 H2O/ACN. Flow rate: 40 ml/min, 30-100, 20 min)to get7-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-dioxa-7-azaspiro[4.4]nonane(24 mg, 0.067 mmol, 15.94% yield). LC-MS (M+H)⁺=358.1. ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 7.31 (2H, t, J=7.63 Hz), 7.20-7.25 (1H, m), 7.15(2H, d, J=7.63 Hz), 4.21 (1H, dd, J=9.16, 6.10 Hz), 4.01-4.06 (4H, m),3.89-3.97 (2H, m), 3.77-3.84 (2H, m), 3.26 (1H, ddd, J=15.03, 8.62, 5.95Hz), 3.13 (1H, ddd, J=14.95, 8.85, 5.80 Hz), 2.53-2.63 (1H, m), 2.17(2H, t, J=7.17 Hz), 2.03-2.12 (1H, m).

Preparation Gp2-chloro-N-(5-isopropyl-2-methylphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (500 mg,1.886 mmol) in NMP (Volume: 7543 n1) was added5-isopropyl-2-methylaniline (281 mg, 1.886 mmol) and DIPEA (329 μl,1.886 mmol). The resulting mixture was brought to 120° C. and stirredfor 2 h. The mixture was then diluted with EtOAc (25 mL), washed withwater (2×10 mL), brine (10 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. Purification by flash chromatography (Silica,Thomson 40 g, 0-35% EtOAc/Hexanes) gave2-chloro-N-(5-isopropyl-2-methylphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(81421-078-01) (220 mg, 0.582 mmol, 30.9% yield). LC-MS (M+H)⁺=378.1. ¹HNMR (500 MHz, MeOD) δ ppm 7.30-7.41 (3H, m), 7.19-7.26 (3H, m), 7.16(2H, d, J=7.93 Hz), 7.11 (1H, d, J=7.63 Hz), 4.27 (1H, t, J=7.63 Hz),2.91 (1H, ddd, J=13.89, 6.87, 6.71 Hz), 2.77-2.86 (1H, m), 2.61-2.76 (2H, m), 2.24 (3H, s), 2.03-2.13 (1H, m), 1.27 (5H, dd, J=7.02, 1.53 Hz).

Preparation H2,4-Dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Intermediate H(1)

1-Cyclopentenyl-4-fluorobenzene

To a 0.5M solution of 4-fluorophenylmagnesium bromide (298 mL, 149 mmol)in THF at 0° C. was carefully added cyclopentanone (13.23 mL, 149 mmol).Upon the end of the addition, the reaction mixture was heated at refluxfor 2 h. Ice (10 g) and 6N aqueous hydrochloric acid were added. Thereaction mixture was extracted with ether. The combined organic extractswere washed with a saturated aqueous solution of sodium hydrogensulfite, a saturated aqueous solution of sodium bicarbonate and water.The organic layer was dried over anhydrous magnesium sulfate andfiltered. The solvent was removed in vacuum and the residue was purifiedby column chromatography on silica gel to give1-cyclopentenyl-4-fluorobenzene (24.155 g, 149 mmol, 100% yield) ascolorless oil. LC-MS (M+H)⁺=163.0. ¹H NMR (500 MHz, CDCl₃) δ ppm7.35-7.42 (2H, m), 6.95-7.02 (2H, m), 6.06-6.13 (1H, m), 2.63-2.71 (2H,m), 2.47-2.56 (2H, m), 1.96-2.06 (2H, m).

Intermediate H(2)

2-(4-Fluorophenyl)cyclopentanone

A mixture of 80% formic acid (100 mL, 2618 mmol) and 30% hydrogenperoxide (23 mL, 149 mmol) was warmed at 40° C. for 10 min. Theresulting solution was carefully added to1-cyclopentenyl-4-fluorobenzene (24.155 g, 149 mmol) under stirring. Thetwo-phase system was initially stirred at room temperature. After acertain period of time, a spontaneous exothermic reaction took place,and the temperature rose to about 50° C. The reaction mixture wasstirred at room temperature for 1 h. The reaction mixture was quenchedby careful addition of a saturated sodium bicarbonate solution. Etherwas added and the content of the separatory funnel was vigorouslyshaken. The organic layer was separated and the aqueous layer wasextracted with ether. The combined organic extracts were dried overanhydrous magnesium sulfate and filtered. The solvent was removed invacuum and the residue was purified by column chromatography on silicagel to give 2-(4-fluorophenyl)cyclopentanone (18.557 g, 104 mmol, 69.9%yield) as colorless oil. LC-MS (M+H)⁺=177.2. ¹H NMR (500 MHz, CDCl₃) δppm 7.12-7.18 (2H, m), 6.98-7.04 (2H, m), 3.29 (1H, dd, J=11.6, 8.5 Hz),2.42-2.54 (2H, m), 2.27 (1H, ddd, J=19.1, 10.5, 8.9 Hz), 2.12-2.20 (1H,m), 2.01-2.12 (1H, m), 1.87-1.99 (1H, m, J=11.7, 11.7, 8.2, 6.3 Hz).

Intermediate H(3)

7-(4-Fluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione

A mixture of 2-(4-fluorophenyl)cyclopentanone (18.557 g, 104 mmol) andcarbonisocyanatidic chloride (19.77 g, 187 mmol) was heated at 58° C.for 1 h and at 130° C. for 2 h. Upon cooling to room temperature, thetarrified reaction mixture was dissolved in ethyl acetate and washedwith saturated aqueous solution of sodium bicarbonate. The organic layerwas separated and the aqueous layer was extracted with ethyl acetate.The combined organic extracts were dried over anhydrous magnesiumsulfate and filtered. The solvent was removed in vacuum and the residuewas purified by column chromatography on silica gel to give7-(4-fluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(13.527 g, 54.7 mmol, 52.5% yield) as brown solid. LC-MS (M+H)⁺=248.1.¹H NMR (500 MHz, CDCl₃) δ ppm 11.80 (1H, br s), 7.31-7.39 (2H, m),7.16-7.22 (2H, m), 4.30-4.38 (1H, m), 2.63-2.73 (1H, m), 2.53-2.63 (2H,m), 1.84-1.95 (1H, m).

Intermediate H(4)

7-(4-Fluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

A solution of7-(4-fluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(13.527 g, 54.7 mmol) in concentrated ammonium hydroxide (150 mL, 3852mmol) was heated at 100° C. in a high-pressure (350 mL) vesselovernight. The reaction mixture was cooled to 0° C. and filtered. Theprecipitate was consecutively washed with water and dried, first—bypassing air through the filter, and then—in pump vacuum to give7-(4-fluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(4.670 g, 18.97 mmol, 34.7% yield). LC-MS (M+H)⁺=247.3. ¹H NMR (500 MHz,CDCl₃) δ ppm 11.70-11.81 (2H, br s), 7.31-7.39 (2H, m), 7.16-7.22 (2H,m), 4.30-4.38 (1H, m), 2.63-2.73 (1H, m), 2.53-2.63 (2H, m), 1.84-1.95(1H, m).

Preparation H2,4-Dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of7-(4-fluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(1 g, 4.06 mmol) in phosphorus oxychloride (11.81 mL, 127 mmol) andN,N-dimethylaniline (3.94 mL, 31.1 mmol) was stirred at 110° C.overnight. The reaction mixture was carefully poured into ice. Once theice melted, the aqueous layer was extracted with dichloromethane. Thecombined organic extracts were dried over anhydrous magnesium sulfateand filtered. The solvent was removed in vacuum and the residue waspurified by column chromatography on silica gel to give2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(700.0 mg, 2.472 mmol, 60.9% yield) as dark burgundy solid. LC-MS(M+H)⁺=283.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.09-7.15 (2H, m), 7.03 (2H,t, J=8.5 Hz), 4.42 (1H, t, J=8.4 Hz), 3.10 (1H, dd, J=9.2, 4.6 Hz), 3.01(1H, d, J=8.2 Hz), 2.73 (1H, d, J=8.9 Hz), 2.15-2.27 (1H, m).

Preparation Ha2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (521 mg, 1.840 mmol) in MeOH (18.400 mL) was added DIPEA(0.803 mL, 4.60 mmol), then 3,3-difluoroazetidine, HCl (358 mg, 2.76mmol). The reaction was allowed to stir at RT for 2 h and was thenconcentrated in vacuo. Purification by flash chromatography (silica,ethyl acetate/hexanes) gave2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(528 mg, 1.554 mmol, 84% yield) as a clear, colorless oil whichcrystallized on standing. LC-MS (M+H)⁺=340.0. ¹H NMR (500 MHz, CDCl₃) δppm 7.05-7.13 (2H, m), 6.94-7.02 (2H, m), 4.60 (4H, td, J=11.75, 4.27Hz), 4.18-4.30 (1H, m), 2.93-3.06 (1H, m), 2.80-2.95 (1H, m), 2.56-2.70(1H, m), 1.96-2.18 (1H, m).

Preparation Hb(1S,4S)-5-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 μL) was added(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane monohydrochloride (115 mg,0.848 mmol) and DIPEA (271 μL, 1.554 mmol). The resulting mixture wasstirred at RT overnight. The reaction mixture was then concentrated invacuo. The resulting oil was purified by flash chromatography (Silica,EtOAc/Hexanes) to give(1S,45)-5-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane(148 mg, 0.428 mmol, 60.6% yield). LC-MS (M+H)⁺=346.1. ¹H NMR (500 MHz,MeOD) δ ppm 7.12-7.21 (2H, m), 7.00-7.08 (2H, m), 5.11-5.21 (1H, m),4.69-4.74 (1H, m), 4.15-4.26 (1H, m), 3.88-3.94 (2H, m), 3.68-3.86 (2H,m), 3.11-3.21 (1H, m), 2.56-2.69 (1H, m), 1.92-2.11 (2H, m), 1.24-1.42(2H, m).

Preparations Hc1 and Hc2

2-chloro-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 μL) was added2-Methylpyrrolidine (82 μL, 0.848 mmol). The resulting mixture wasstirred at RT for 2 days. The reaction mixture was then concentrated invacuo. The resulting oil was purified by flash chromatography (Silica,EtOAc/Hexanes) to give two racemic pairs of diasteriomers2-chloro-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.(Hc1, Diastereomer 1, racemic, first to elute) (79.5 mg, 0.240 mmol,33.9% yield). LC-MS (M+H)⁺=332.1; ¹H NMR (500 MHz, MeOD) δ ppm 7.16 (2H,d, J=5.49 Hz), 7.04 (2H, s), 4.42-4.54 (1H, m), 4.09-4.22 (1H, m),3.86-4.00 (1H, m), 3.71-3.82 (1H, m), 3.24-3.31 (1H, m), 3.10-3.22 (1H,m), 2.54-2.65 (1H, m), 2.05-2.16 (2H, m), 1.94-2.05 (2H, m), 1.69-1.80(1H, m), 1.27 (3H, d, J=6.10 Hz). (Hc2, Diastereomer 2, racemic, secondto elute) (89.5 mg, 0.270 mmol, 38% yield). LC-MS (M+H)⁺=332.1; ¹H NMR(500 MHz, MeOD) δ ppm 7.14 (2H, d, J=5.49 Hz), 6.99-7.08 (2H, m),4.42-4.54 (1H, m), 4.13-4.22 (1H, m), 3.86-4.00 (1H, m), 3.71-3.83 (1H,m), 3.25-3.32 (1H, m), 3.14-3.25 (1H, m), 2.52-2.67 (1H, m), 2.05-2.19(2H, m), 1.94-2.05 (2H, m), 1.68-1.78 (1H, m), 1.19-1.32 (3H, m). Therelative stereochemistry for Hc1 and Hc2 was not determined

Preparation Hd(2S,6R)-4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,6-dimethylmorpholine

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 μL) was addedcis-2,6-Dimethylmorpholine (105 μL, 0.848 mmol). The resulting mixturewas stirred at RT overnight. An additional 2 equ. ofcis-2,6-Dimethylmorpholine was then added and the mixture was againstirred overnight at RT. The reaction mixture was then concentrated invacuo. The resulting oil was purified by flash chromatography (Silica,EtOAc/Hexanes) to give(2S,6R)-4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,6-dimethylmorpholine(223 mg, 0.616 mmol, 87% yield). LC-MS (M+H)⁺=332.1. ¹H NMR (500 MHz,MeOD) δ ppm 7.11-7.24 (2H, m), 6.99-7.09 (2H, m), 4.39-4.51 (2H, m),4.20 (1H, s), 3.70 (2H, td, J=4.12, 2.44 Hz), 3.14-3.25 (1H, m),3.03-3.13 (1H, m), 2.69-2.80 (2H, m), 2.54-2.68 (1H, m), 1.95-2.13 (1H,m), 1.23 (6H, d, J=6.10 Hz).

Preparation He1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation 11) (400 mg, 1.413 mmol) in MeOH (14.100 mL) was added4-methylpiperidin-4-ol (163 mg, 1.413 mmol). The resulting mixture wasstirred at RT overnight. The reaction mixture was then concentrated invacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol(374 mg, 1.034 mmol, 73.2% yield). LC-MS (M+H)⁺=362.0. ¹H NMR (500 MHz,MeOD) δ ppm 7.12-7.21 (2H, m), 7.04 (2H, t, J=8.85 Hz), 4.11-4.30 (3H,m), 3.48-3.63 (2 H, m), 3.14-3.23 (1H, m), 3.00-3.12 (1H, m), 2.54-2.66(1H, m), 1.94-2.09 (1H, m), 1.68 (4H, t, J=4.12 Hz), 1.28 (3H, s).

Preparations Hf1 and Hf2

2-chloro-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (200 mg, 0.706 mmol) and 2-ethylpyrrolidine (84 mg,0.848 mmol) were combined and purified as per Preparation Hd to give twopairs of racemic diasteriomers2-chloro-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine.(Hf1, Diastereomer 1, racemic, first to elute) (77 mg, 0.223 mmol, 32%yield) LC-MS (M+H)⁺=346. (Hf2, Diastereomer 2, racemic, second to elute)(80 mg, 0.232 mmol, 33% yield); LC-MS (M+H)⁺=346.2. The relativestereochemistry for Hf1 and Hf2 was not determined

Preparation Hg tert-butyl1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ylcarbamate

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (400 mg, 1.413 mmol) in MeOH (14.100 mL) was addedtert-butyl 4-methylpiperidin-4-ylcarbamate (303 mg, 1.413 mmol). Theresulting mixture was stirred at RT for 7 days. At that time, thereaction mixture was concentrated in vacuo. Purification by flashchromatography (Silica, EtOAc/Hexanes) gave tert-butyl1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ylcarbamate(159 mg, 0.345 mmol, 24.41% yield) as a yellow foam. LC-MS (M+H)⁺=461.2.¹H NMR (500 MHz, MeOD) δ ppm 7.12-7.22 (2H, m), 6.98-7.09 (2H, m), 4.19(3H, d, J=2.14 Hz), 3.38-3.56 (2H, m), 3.13-3.25 (1H, m), 3.02-3.13 (1H,m), 2.53-2.67 (1H, m), 2.11-2.24 (2H, m), 1.96-2.08 (1H, m), 1.53-1.65(2H, m), 1.47 (9H, s), 1.37 (3H, s).

Preparation Hh2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (500 mg, 1.766 mmol) and methanamine hydrochloride (179mg, 2.65 mmol) were combined and purified as per Preparation Ha to give2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(344 mg, 1.239 mmol, 70.1% yield). LC-MS (M+H)⁺=278.0. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.03-7.12 (2H, m), 6.91-7.03 (2H, m), 4.53-4.79 (1H, m),4.19-4.29 (1H, m), 3.09 (3H, d, J=4.88 Hz), 2.56-2.80 (3H, m), 2.00-2.15(1H, m).

Preparation Hi1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (286 mg, 1.010 mmol) and3-(trifluoromethyl)pyrrolidin-3-ol (157 mg, 1.010 mmol) were combinedand purified as per Preparation Hb to give1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-01(62% yield). LC-MS (M+H)⁺=402.0.

Preparation Hj1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N,N-dimethylpyrrolidin-3-amine

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (100 mg, 0.353 mmol) and N,N-dimethylpyrrolidin-3-amine(44.3 μL, 0.353 mmol) were combined and purified as per Preparation Hbto give1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N,N-dimethylpyrrolidin-3-amine(109 mg, 86% yield). LC-MS (M+H)⁺=361.2.

Preparation Hk2-chloro-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (100 mg, 0.353 mmol) and 1-methylpiperazine (39.2 μL,0.353 mmol) were combined and purified as per Preparation Hb to give2-chloro-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(109 mg, 0.314 mmol, 89% yield). LC-MS (M+H)⁺=347.2.

Preparation Hl tert-butyl4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (100 mg, 0.353 mmol) and tert-Butyl1-piperazinecarboxylate (65.8 mg, 0.353 mmol) were combined and purifiedas per Preparation Hb to give tert-butyl4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(116.9 mg, 76% yield). LC-MS (M+H)⁺=433.3.

Preparation Hm tert-butyl1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-ylmethyl)carbamate

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (100 mg, 0.353 mmol) and3-(N-tert-Butoxycarbonyl-N-methylamino)pyrrolidine (69.4 μL, 0.353 mmol)were combined and purified as per Preparation Hb to give tert-butyl1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-ylmethyl)carbamate(148 mg, 94% yield). LC-MS (M+H)⁺=447.2.

Preparation Hn tert-butyl1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate

2,4-Dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (100 mg, 0.353 mmol) and carbamic acid,3-azetidinylmethyl-, 1,1-dimethylethyl ester (82 mg, 0.441 mmol) werecombined and purified as per Preparation Hb to give tert-butyl1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate(147 mg, 96% yield). LC-MS (M+H)⁺=377.1.

Preparation Ho1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N,N-dimethylazetidin-3-amine

2,4-Dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (100 mg, 0.353 mmol) and N,N-dimethylazetidin-3-amine,2HCl (122 mg, 0.706 mmol) were combined and purified as per PreparationHb to give1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N,N-dimethylazetidin-3-amine(quantitative). LC-MS (M+H)⁺=347.2.

Preparation Hp1 and Hp22-chloro-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidine

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (135 mg, 0.477 mmol) in MeOH (4768 μL) was added DIPEA(208 μL, 1.192 mmol), then (S)-3-fluoropyrrolidine (46.7 mg, 0.524mmol). The reaction was allowed to stir at ambient temperature for 2 h.The solvent was removed and the residue applied to Silica gel and elutedwith an EtOAc/Hex gradient to afford two diasteriomers (Hp1 and Hp2).Hp1: LC-MS (M+H)⁺=336.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.06-7.13 (2H,m), 6.93-7.00 (2H, m), 5.32 (1H, td, J=52.57, 3.17 Hz), 4.17 (1H, dd,J=9.16, 5.49 Hz), 4.06-4.14 (1H, m), 3.98-4.06 (1H, m), 3.76-3.90 (2H,m), 3.25 (1H, ddd, J=15.11, 8.55, 6.26 Hz), 3.08-3.16 (1H, m), 2.51-2.60(1H, m, J=13.20, 9.12, 9.12, 6.41 Hz), 2.32-2.42 (1H, m), 2.00-2.17 (2H,m). Hp2: LC-MS (M+H)⁺=336.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.06-7.14(2H, m), 6.94-7.02 (2H, m), 5.25-5.40 (1H, m), 3.99-4.24 (3H, m),3.75-3.92 (2H, m), 3.19-3.28 (1H, m), 3.10-3.19 (1H, m), 2.57 (1H, dddd,J=13.24, 8.74, 8.55, 4.58 Hz), 2.31-2.43 (1H, m), 1.94-2.17 (2H, m)

Preparation Hq2-chloro-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidine

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) was reacted as described in Preparation Hp1 and Hp2 with(R)-3-fluoropyrrolidine. The solvent was removed and the residue appliedto Silica gel and eluted with an EtOAc/Hex gradient to afford thecombined two diasteriomers (Hq). Ha1: LC-MS (M+H)⁺=336.0.

Preparation Hr2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (90 mg, 0.318 mmol) in MeOH (3179 μL),4,4-difluoropiperidine (115 mg, 0.95 mmol) was added. The reaction wasallowed to stir at rt. When the reaction was complete, removed solventand applied residue to Silica gel. Eluted with EtOAc/Hex to afford thedesired2-chloro-4-(4,4-difluoropiperidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(80.8 mg, 0.220 mmol, 69.1% yield). LC-MS (M+H)⁺=368.0.

Preparation Hs2-chloro-4-(4-fluoro-5,6-dihydropyridin-1(2H)-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) was reacted as described in Preparation Hc with4-fluoro-1,2,3,6-tetrahydropyridine to afford2-chloro-4-(4-fluoro-5,6-dihydropyridin-1(2H)-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation Hs).

Preparation Ht2-chloro-7-(4-fluorophenyl)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) was reacted as described in Preparation Hr with3-trifluoromethylpyrrolidine to afford2-chloro-7-(4-fluorophenyl)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation Ht) as a mixture of 4 diasteriomers. LC-MS (M+H)⁺=386.1. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.05-7.11 (2H, m), 6.96 (2H, t, J=8.70 Hz),4.14-4.20 (1H, m), 3.89-4.02 (2H, m), 3.75-3.86 (2H, m), 3.17-3.28 (1H,m), 3.06-3.16 (1H, m), 2.99 (1H, dq, J=15.95, 8.01 Hz), 2.50-2.61 (1H,m), 2.13-2.30 (2H, m), 1.95-2.06 (1H, m)

Preparation Hu2-chloro-N-(3-ethoxypropyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) was reacted as described in Preparation Hr with3-ethoxypropan-1-amine to afford2-chloro-N-(3-ethoxypropyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Hu). LC-MS (M+H)⁺=350.1.

Preparation Hv3-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)propan-1-ol

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) was reacted as described in Preparation Hr with3-hydroxypropan-1-amine to afford3-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)propan-1-ol(Preparation Hv). LC-MS (M+H)⁺=322.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.08(2H, dd, J=8.55, 5.49 Hz), 6.97 (2H, t, J=8.70 Hz), 5.18 (1H, br. s.),4.22-4.27 (1H, m), 3.66-3.75 (4H, m), 3.18 (1H, br. s.), 2.60-2.77 (3H,m), 2.02-2.12 (1H, m), 1.78-1.86 (2H, m)

Preparation Hw2-chloro-N-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) was reacted as described in Preparation Hr with1-cyclopropyl-2-methoxyethanamine to afford2-chloro-N-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Hw) as a mixture of 4 diasteriomers. LC-MS (M+H)⁺=362.1.

Preparation Hx2-Chloro-7-(4-fluorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(260 mg, 0.918 mmol) and excess dimethylamine (4.59 mL, 9.18 mmol) inmethanol (2 mL) was stirred at rt for 30 min. The solvent was removed invacuum to afford crude2-chloro-7-(4-fluorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(268 mg, 0.919 mmol, 100% yield). LC-MS (M+H)⁺=292.3.

Preparation Hy2-Chloro-7-(4-fluorophenyl)-N-trideuteromethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(350 mg, 1.236 mmol) and trideuteromethylamine hydrochloride (174 mg,2.472 mmol) in methanol (3 mL) was added DIPEA (0.432 mL, 2.472 mmol).The reaction mixture was stirred at room temperature overnight. Thesolvent was removed in vacuum and the residue was purified by columnchromatography on silica gel to give2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(350 mg, 1.236 mmol) as brown oil. LC-MS (M+H)⁺=281.2.

Preparation Hz2-chloro-7-(4-fluorophenyl)-N—((R)-1-methoxybutan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a mixture of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (100 mg, 0.353 mmol) in THF (1766 μL) was added(R)-1-methoxybutan-2-amine, HCl (197 mg, 1.413 mmol) and DIEA (493 μL,2.83 mmol). The mixture was heated at 60° C. for 3 days. The crudeproduct was purified by Prep-HPLC to get2-chloro-7-(4-fluorophenyl)-N—((R)-1-methoxybutan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Hz) (78 mg, 0.223 mmol, 63.1% yield). LC-MS (M+H)⁺=350.4.¹H NMR (500 MHz, CDCl₃) δ ppm 7.12 (dd, J=8.24, 5.49 Hz, 2H) 6.87-7.05(m, 2H) 4.86 (d, J=7.63 Hz, 1H) 4.35 (d, J=3.05 Hz, 1 H) 4.18-4.30 (m,1H) 3.47-3.60 (m, 2H) 3.40 (d, J=6.71 Hz, 3H) 2.62-2.82 (m, 3H)2.03-2.15 (m, 1H) 1.58-1.78 (m, 2H) 0.89-1.07 (m, 3H).

Preparation Haa2-chloro-N—((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) (100 mg, 0.353 mmol) in THF (1766 μL) was added(R)-1-cyclopropylethanamine, HCl (172 mg, 1.413 mmol) and DIEA (493 μL,2.83 mmol). The mixture was stirred at 60° C. for 5 days. The crudeproduct was purified by Prep-HPLC get2-chloro-N—((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Haa) (74 mg, 0.223 mmol, 63.1% yield). LC-MS (M+H)⁺=332.3.¹H NMR (500 MHz, CDCl₃) δ ppm 7.06-7.18 (m, 2 H) 7.00 (td, J=8.70, 1.53Hz, 2H) 4.65 (d, J=5.80 Hz, 1H) 4.26 (t, J=7.17 Hz, 1H) 3.63-3.79 (m,1H) 2.62-2.82 (m, 3H) 2.04-2.16 (m, 1H) 1.26-1.40 (m, 3H) 0.94 (qd,J=8.24, 3.36 Hz, 1H) 0.42-0.62 (m, 3H) 0.24-0.40 (m, 1H).

Preparation Hab2-chloro-N—((S)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation H) was reacted as described in Preparation Haa with(S)-1-cyclopropylethanamine, HCl to give2-chloro-N—((S)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Hab). LC-MS (M+H)⁺=332.3. ¹H NMR (500 MHz, CDCl₃) δ ppm7.07-7.21 (m, 2H) 6.93-7.07 (m, 2H) 4.65 (d, J=5.80 Hz, 1H) 4.26 (t,J=7.32 Hz, 1H) 3.61-3.79 (m, 1H) 2.62-2.82 (m, 3H) 2.05-2.16 (m, 1H)1.25-1.39 (m, 3H) 0.84-1.00 (m, 1H) 0.42-0.62 (m, 3H) 0.29-0.40 (m, 1H).

Preparation Hac1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylazetidine-3-carbonitrile

3-cyano-3-methylazetidine was reacted with Preparation H in the mannerof Preparation Gi to afford the title compound. LC-MS (M+H)⁺=343.0 ¹HNMR (500 MHz, CHLOROFORM-d) δ ppm 6.96-7.13 (m, 5H) 4.73 (d, J=6.71 Hz,1H) 4.35 (d, J=7.32 Hz, 2H) 4.33 (br. s., 1H) 4.27 (dd, J=9.00, 2.90 Hz,1H) 2.99-3.09 (m, 1H) 2.85-2.99 (m, 1H) 2.64-2.78 (m, 1H) 2.11 (dd,J=13.89, 7.48 Hz, 1H) 1.76-1.91 (m, 3H).

Preparation Had2-chloro-4-(3-ethoxyazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

3-ethoxyazetidine was reacted with Preparation H in the manner ofPreparation Gi to afford the title compound. LC-MS (M+H)⁺=348.0 ¹H NMR(500 MHz, CHLOROFORM-d) δ ppm 7.03-7.12 (m, 2H) 6.91-7.01 (m, 2H) 4.51(br. s., 2H) 4.36-4.48 (m, 1H) 4.13-4.32 (m, 3H) 3.50 (qd, J=6.97, 3.20Hz, 2H) 2.97-3.10 (m, 1 H) 2.82-2.96 (m, 1H) 2.51-2.70 (m, 1H) 1.93-2.11(m, 1H) 1.16-1.35 (m, 3H).

Preparation Hae1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylazetidin-3-ol

3-methylazetidin-3-ol was reacted with Preparation H in the manner ofPreparation Gi to afford the title compound. LC-MS (M+H)⁺=334.0 ¹H NMR(500 MHz, CHLOROFORM-d) δ ppm 7.04-7.13 (m, 2H) 7.00 (t, J=8.55 Hz, 2H)4.41 (d, J=6.71 Hz, 2H) 4.39 (br. s., 3H) 3.05-3.17 (m, 1H) 2.90-3.04(m, 1H) 2.73 (ddd, J=9.08, 4.88, 4.65 Hz, 1H) 2.03-2.19 (m, 1H) 1.65 (s,3H).

Preparation Haf2-chloro-7-(4-fluorophenyl)-4-(3-methoxy-3-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

3-methoxy-3-methylazetidine was reacted with Preparation H in the mannerof Preparation Gi to afford the title compound. LC-MS (M+H)⁺=348.

Preparation I2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

Intermediate I(1)

3-iodo-4,4-dimethoxytetrahydro-2H-pyran

To a mixture of tetrahydro-4H-pyran-4-one (18.52 mL, 200 mmol) andtrimethyl orthoformate (100 mL, 914 mmol) at 0° C. was added Iodine(49.2 mL, 200 mmol) slowly over 10 min. When the addition was complete,the reaction mixture was allowed to stir at 0° C. for 30 min. and wasthen allowed to come to RT and stir until TLC indicated all startingmaterial had been consumed (approx. 1 h). The reaction was then cooledto 0° C. and quenched by the slow addition of sat. aqu. sodiumthiosulfate (300 mL). The resulting mixture was extracted with EtOAc(3×75 mL). The combined organic layers were washed with brine (100 mL),dried over MgSO₄, filtered and concentrated in vacuo. Purification byflash chromatography (Silica, EtOAc/Hexanes) gave3-iodo-4,4-dimethoxytetrahydro-2H-pyran (43.95 g, 162 mmol, 81% yield)as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 4.25 (1H, q, J=2.44 Hz),3.93-4.01 (1H, m), 3.84-3.93 (2H, m), 3.57 (1H, td, J=11.75, 2.44 Hz),3.19-3.30 (6H, m), 2.34 (1H, ddd, J=14.34, 12.21, 4.88 Hz), 1.80 (1H,dq, J=14.34, 2.44 Hz).

Intermediate I(2)

3-phenyldihydro-2H-pyran-4(3H)-one

To a stirred mixture of phenylboronic acid (16.81 g, 138 mmol),trans-2-Aminocyclohexanol hydrochloride (1.393 g, 9.19 mmol), andNickel(II) chloride hexahydrate (1.092 g, 4.59 mmol) in THF (92 mL) at0° C. was added Sodium bis(trimethylsilyl)amide (1.0 M in THF) (184 mL,184 mmol) dropwise over 10 min. When the addition was complete, thereaction mixture was sparged with N₂ for 15 min. To the reaction mixtureat 0° C. was then added 2-Propanol (375 mL)(previously sparged with N₂).The resulting mixture was allowed to come to RT at which time3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate 41)) (25 g, 92mmol) was added dropwise over 5 min. The reaction mixture was thenbrought to 60° C. and stirred overnight. The reaction mixture was thencooled to 0° C. and quenched by the careful addition of aqu. 1 N HCluntil acidic. The resulting mixture was extracted with EtOAc (3×150 mL).The combined organic extracts were washed with Brine (100 mL), driedover MgSO₄, filtered and concentrated in vacuo. Purification by flashchromatography (Silica, EtOAc/Hexanes) gave3-phenyldihydro-2H-pyran-4(3H)-one (8.37 g, 47.5 mmol, 51.7% yield) as aslightly orange oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.32-7.39 (2H, m),7.26-7.31 (1H, m), 7.21-7.26 (2H, m), 4.17-4.31 (2H, m), 3.91-4.05 (2H,m), 3.78 (1H, dd, J=8.55, 6.10 Hz), 2.61-2.74 (1H, m), 2.51-2.61 (1H,m).

Intermediate I(3)

8-phenyl-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione

A mixture of 3-phenyldihydro-2H-pyran-4(3H)-one (Intermediate I(2)) (3g, 17.02 mmol) and carbonisocyanatidic chloride (10.48 g, 29.8 mmol) ina sealed tube was heated to 58° C. and stirred for 1 h. The mixture wasthen brought to 130° C. and stirred for an additional 2 h. The reactionturned black during this time. After cooling to RT, the tar was taken upin EtOAc (100 mL). The resulting solution was washed with saturatedaqueous sodium bicarbonate (2×50 mL), brine (50 mL), dried over MgSO₄,filtered and concentrated in vacuo. Purification by flash chromatography(Silica, EtOAc/Hexanes) gave8-phenyl-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (2.58 g,10.52 mmol, 61.8% yield) as a brown solid. LC-MS (M+H)⁺=246.0. ¹H NMR(500 MHz, MeOD) δ ppm 7.34-7.41 (4H, m), 7.29-7.34 (1H, m), 4.42-4.63(2H, m), 4.08-4.15 (1H, m), 3.94 (1H, dd, J=11.44, 4.12 Hz), 3.85 (1H,ddd, J=4.20, 2.44, 2.21 Hz).

Intermediate I(4)

8-phenyl-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione

A solution of8-phenyl-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione(Intermediate 43)) (2.58 g, 10.52 mmol) in ammonium hydroxide (28.7 mL,736 mmol) was heated to 80° C. in a sealed tube and stirred overnight.The reaction mixture was then concentrated to dryness giving8-phenyl-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione. Thecrude material was carried on as-is. LC-MS (M+H)⁺=245.2.

Preparation I

2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

A mixture of8-phenyl-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione(Intermediate 44)) (2569 mg, 10.52 mmol) and POCl₃ (29.400 mL, 315 mmol)was heated to 100° C. under microwave irradiation in a sealed tube for 1h. The resulting mixture was poured over ice. When all the ice wasmelted, the mixture was extracted with EtOAc (3×15 mL). The combinedorganic extracts were washed with brine (20 mL), dried over MgSO₄,filtered and concentrated in vacuo. Purification by flash chromatography(Silica, EtOAc/Hexanes) gave2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (194 mg,0.690 mmol, 6.56% yield). LC-MS (M+H)⁺=281.1. ¹H NMR (500 MHz, MeOD) δppm 7.30-7.37 (2H, m), 7.25-7.30 (1H, m), 7.18-7.25 (2H, m), 4.90-5.00(1H, m), 4.75-4.84 (1H, m), 4.16-4.26 (2H, m), 4.02-4.15 (1H, m).

Preparation Ia

2-chloro-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

To a solution of2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation I) (194 mg, 0.690 mmol) in MeOH (6901 μL) was addedmethanamine hydrochloride (69.9 mg, 1.035 mmol) andN,N-Diisopropylethylamine (301 μL, 1.725 mmol). The resulting mixturewas stirred at RT for 2 h. The reaction mixture was then concentrated invacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave2-chloro-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(126 mg, 0.457 mmol, 66.2% yield). LC-MS (M+H)⁺=276.0. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.28 (2H, t, J=7.32 Hz), 7.20-7.25 (1H, m), 7.14-7.20 (2H,m), 4.47-4.62 (2H, m), 4.47 (1H, s), 4.00-4.11 (2H, m), 3.95 (1H, d,J=3.36 Hz), 3.08 (3H, d, J=4.88 Hz).

Preparation Ib2-Chloro-N,N-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

A solution of2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (135 mg,0.480 mmol) and excess dimethylamine (216 mg, 4.80 mmol) in MeOH (2 mL)was stirred at rt for 1.5 h. The solvent was removed in vacuum to afford2-chloro-N,N-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(139 mg, 0.480 mmol, 100% yield). LC-MS (M+H)⁺=290.3.

Preparation Ic2-Chloro-N-ethyl-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

A solution of2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (135 mg,0.480 mmol) and excess N-methylethanamine (284 mg, 4.80 mmol) in MeOH (2mL) was stirred at rt for 1 h. The solvent was removed in vacuum toafford2-chloro-N-ethyl-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(146 mg, 0.481 mmol, 100% yield). LC-MS (M+H)⁺=304.2.

Preparation J:2,4-dichloro-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

Intermediate J(1):

3-bromodihydro-2H-pyran-4(3H)-one

To a cooled solution of dihydro-2H-pyran-4(3H)-one (10.0 g, 99.8 mmol)in THF was added a solution of pyrrolidone hydrotribromide (49.54 g,99.8 mmol) in THF over a period of 10 min. at 0° C. The reaction mixturewas allowed to come to room temperature and stirred for 2 h. The solventwas removed under reduced pressure and the residue was diluted withethyl acetate (300 mL). The organic solution was washed with aqueoussaturated NaHCO₃ (100 mL), water (100 mL×2), brine solution (50 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure togive 3-bromodihydro-2H-pyran-4(3H)-one (12.0 g, 67%) as oily liquid. Thecrude compound was taken to the next step without further purification.¹H NMR (400 MHz, DMSO-d6): δ ppm 4.89-4.87 (1H, m) 4.28-4.27 (1H, m)4.25-4.4.24 (1H, m) 3.85-3.74 (2H, m) 2.71-2.66 (2H, m).

Intermediate J(2):

3-(4-fluorophenyl)dihydro-2H-pyran-4(3H)-one

To a solution of Intermediate J(1) (12.0 g, 66.9 mmol) in benzene wasadded 2 M solution of 4-fluorophenyl magnesium bromide in ether (13.34g, 33.48 mL, 66.9 mmol) at 0° C. The reaction mixture was stirred atroom temperature for 40 min. The reaction mixture was quenched withaqueous 1.5 N HCl (80 mL). The organic layer was separated and theaqueous layer was extracted with ethyl acetate (100×2). The combinedorganic layer was washed with water (100 mL×2), brine solution (50 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure togive crude compound as oily liquid. The crude compound was dissolved inbenzene and was added a solution of 4-fluorophenyl magnesium bromide inether (9.7 g, 24.5 mL, 49.0 mmol) at 0° C. The reaction mixture washeated at reflux for 30 min. The reaction mixture was quenched withaqueous 1.5 N HCl (50 mL). The organic layer was separated and theaqueous layer was extracted with ethyl acetate (100×2). The combinedorganic layer was washed with water (100 mL×2), brine solution (50 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure togive crude compound. The crude compound was purified by columnchromatography (Silica gel, 230-400 mesh) using 5% ethyl acetate inpet-ether as mobile phase to give3-(4-fluorophenyl)dihydro-2H-pyran-4(3H)-one (3.0 g, 36%) as oilyliquid. LC-MS (M+H)⁺=195.2. ¹H NMR (400 MHz, chloroform-d): δ ppm7.7.21-7.18 (2H, m), 7.06-7.01 (2H, m), 4.28-4.21 (2H, m), 3.99-3.91(2H, m), 3.79-3.76 (1H, m) 2.72-2.67 (1H, m) 2.64-2.55 (1H, m).

Intermediate J(3)

8-(4-fluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione

A solution of Intermediate J(2) (1.5 g, 7.72 mmol) and N-chlorocarbonylisocyanate (0.97 g, 9.2 mmol) was heated at 58° C. under nitrogenatmosphere for 1 h. Then, the reaction temperature was increased to 130°C. and maintained for 2 h. The reaction mass was diluted with ethylacetate (50 mL). The resulting organic solution was washed withsaturated NaHCO₃ (25 mL), brine solution (25 mL), dried over anhydrousNa₂SO₄ and evaporated under reduced pressure to get crude compound. Thecrude compound was purified by column chromatography (Silica gel, 60-120mesh) using 50% ethyl acetate in pet-ether as mobile phase to give8-(4-fluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione(0.8 g, 38%) as brown solid. LC-MS (M−H)⁺=262.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 11.97 (1H, s), 7.43-7.39 (2H, m), 7.21-7.16 (2H, m),4.48-4.32 (2H, m), 4.05 (2H, m), 3.77 (1H, m).

Intermediate J(4)

8-(4-fluorophenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione

A solution of Intermediate J(3) (0.8 g, 3.0 mmol) in aqueous ammonia (50mL) was heated at reflux for 18 h. The excess ammonia was removed underreduced pressure and the aqueous solution was extracted with ethylacetate (25 mL×4). The combined organic layer was washed with brinesolution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to give8-(4-fluorophenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione(0.4 g, 50%). The crude compound was taken to the next step withoutfurther purification. LC-MS (M+H)⁺=263.4. ¹H NMR (400 MHz, DMSO-d6): δppm 11.16 (1H, s), 10.79 (1H, s), 7.33-7.29 (2H, m), 7.19-7.15 (2H, m),4.43 (1H, m), 4.25 (1H, m), 3.90 (1H, m), 3.75-3.68 (2H, m).

Preparation J2,4-dichloro-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

A solution of Intermediate J(4) (0.7 g, 2.6 mmol) and catalytic amountof DMF in POCl₃ (20 vol.) was heated at reflux for 18 h. The excess ofPOCl₃ was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 min. The aqueous solution wasextracted with ethyl acetate (20 mL×2). The combined organic layer waswashed with aqueous saturated NaHCO₃ (50 mL×2), brine solution (25 mL),dried over Na₂SO₄ and evaporated under reduced pressure to give2,4-dichloro-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(0.79 g) as crude compound. The crude compound was taken to the nextstep without further purification. LC-MS (M+H)⁺=299.0.

Preparation Ja2-chloro-8-(4-fluorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

To a solution of Preparation J (0.7 g, 2.3 mmol) in methanol was addedCs₂CO₃ (1.49 g, 4.6 mmol) followed by addition of methylaminehydrochloride (0.78 g, 11.7 mmol) at room temperature. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under reduced pressure and the residue diluted with ethylacetate (25 mL), washed with water (25 mL), brine solution (25 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by column chromatography(60-120 mesh) using 50% ethyl acetate in pet-ether as mobile phase togive2-chloro-8-(4-fluorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(0.34 g, 49%) as off-white solid. LC-MS (M+H)⁺=294.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 7.22-7.19 (2H, m), 7.13-7.07 (2H, m), 4.91 (1H, m), 4.75(1H, m), 4.12-4.08 (2H, m), 3.74 (1H, m), 3.05 (6H, s).

Preparation Jb2-chloro-N-ethyl-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

To a solution of Preparation J (0.350 g, 1.17 mmol) in methanol wasadded diisopropylethylamine (0.30 g, 2.2 mmol) followed by ethylaminehydrochloride (0.113 g, 1.17 mmol) at room temperature. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under reduced pressure and the residue diluted with ethylacetate (25 mL), washed with water (25 mL), brine solution (25 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by column chromatography(60-120 mesh) using 50-55% ethyl acetate in pet-ether as mobile phase togive2-chloro-N-ethyl-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(0.16 g, 60%) as off-white solid. LC-MS (M+H)⁺=308.2.

Preparation Jc1 and Jc22-chloro-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

To a solution of Preparation J (0.70 g, 2.34 mmol) in methanol was addeddiisopropylethylamine (0.60 g, 4.6 mmol) followed by(R)-3-fluoropyrrolidine (0.58 g, 4.6 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified byprep-HPLC (40% ethanol in hexane) to give2-chloro-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(0.90 g, 11% Isomer 1, 0.110 g, 13% Isomer 2) as off-white solid. LC-MS(M+H)⁺=352.2. ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.24 (2H, m), 7.13 (2H,m), 5.40 (1H, m), 4.12 (1H, d, J=14.8 Hz), 4.88 (1H, d, J=14.8 Hz),4.14-4.09 (2H, m), 3.91-3.81 (3H, m), 3.75-3.66 (2H, m), 2.51-2.18 (2H,m).

Preparation Jd1 and Jd22-chloro-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

To a solution of Preparation J (0.70 g, 2.34 mmol) in methanol was addeddiisopropylethylamine (0.60 g, 4.6 mmol) followed by(S)-3-fluoropyrrolidine (0.58 g, 4.6 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified byprep-HPLC (40% ethanol in hexane) to give2-chloro-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(0.100 g, 12% Isomer 1, 0.110 g, 13% Isomer 2) as off-white solid. LC-MS(M+H)⁺=352.2.

Jd1: ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.24 (2H, m), 7.13 (2H, m), 5.40(1H, m), 4.12 (1H, d, J=14.4 Hz), 4.88 (1H, d, J=14.4 Hz), 4.11 (2H, m),3.94-3.89 (3H, m), 3.72-3.58 (2H, m), 2.20-2.01 (2H, m).

Jd2: ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.21 (2H, m), 7.13 (2H, m), 5.39(1H, m), 5.02 (2H, m), 4.02-3.97 (2H, m), 3.91-3.84 (4H, m), 3.73 (1H,m), 2.23-2.01 (2H, m).

Preparation Je2-chloro-8-(4-fluorophenyl)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

To a solution of Preparation J (0.7 g, 2.3 mmol) in methanol was addedCs₂CO₃ (1.49 g, 4.6 mmol) followed by addition of dimethylaminehydrochloride (0.95 g, 11.7 mmol) at room temperature. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under reduced pressure and the residue diluted with ethylacetate (50 mL), washed with water (25 mL), brine solution (25 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by column chromatography(60-120 mesh) using 40% ethyl acetate in pet-ether as mobile phase togive2-chloro-8-(4-fluorophenyl)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(0.35 g, 49%) as off-white solid. LC-MS (M+H)⁺=308.2. This compound wastaken to the next step without further purification.

Preparation Jf2-chloro-N-ethyl-8-(4-fluorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

To a solution of Preparation J (0.7 g, 2.3 mmol) in methanol was addedCs₂CO₃ (1.49 g, 4.6 mmol) followed by addition of ethylmethylaminehydrochloride (1.1 g, 11.7 mmol) at room temperature. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under reduced pressure and the residue diluted with ethylacetate (25 mL), washed with water (25 mL), brine solution (25 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by column chromatography(60-120 mesh) using 50% ethyl acetate in pet-ether as mobile phase togive2-chloro-N-ethyl-8-(4-fluorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(0.39 g, 52%) as off-white solid. LC-MS (M+H)⁺=322.2. This compound wastaken to the next step without further purification.

Preparation Jg2-chloro-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

To a solution of Preparation J (0.7 g, 2.3 mmol) in methanol was addedCs₂CO₃ (1.49 g, 4.6 mmol) followed by addition of 3,3-difluoroazetidinehydrochloride (0.60 g, 4.6 mmol) at room temperature. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under reduced pressure and the residue diluted with ethylacetate (25 mL), washed with water (25 mL), brine solution (25 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by column chromatography(60-120 mesh) using 50% ethyl acetate in pet-ether as mobile phase togive2-chloro-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(0.42 g, 50%) as off-white solid. LC-MS (M+H)⁺=355.2. This compound wastaken to the next step without further purification.

Preparation K2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

The title compound was prepared in the analogous fashion to PreparationJ, as a pale yellow solid. LC-MS (M+H)⁺=315.0. ¹H NMR (400 MHz, CDCl₃) δppm 7.30 (2H, dd, J=2.0, 6.4 Hz), 7.17 (2H, dd, J=2.0, 6.4 Hz), 4.91(1H, d, J=16.4 Hz), 4.76 (1H, d, J=16.0 Hz), 4.18-4.09 (3H, m).

Preparation Ka 2-chloro-8-(4-chlorophenyl)-4-(3,3-di fluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation K) (500 mg, 1.584 mmol) and 3,3-Difluoroazetidinehydrochloride (308 mg, 2.377 mmol) were combined and purified as perPreparation Ha to give 2-chloro-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (400 mg, 1.075mmol, 67.8% yield) as a white solid. LC-MS (M+H)⁺=372.0. ¹H NMR (500MHz, CDCl₃) δ ppm 7.22-7.34 (2H, m), 7.12 (2H, d, J=8.24 Hz), 4.63-4.85(2H, m), 4.46-4.64 (3H, m), 4.04-4.17 (1H, m), 3.91-4.04 (2H, m).

Preparation Kb2-chloro-8-(4-chlorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation K) (500 mg, 1.584 mmol) and methanamine hydrochloride (160mg, 2.377 mmol) were combined and purified as per Preparation Ha to give2-chloro-8-(4-chlorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(150 mg, 0.484 mmol, 30.5% yield). LC-MS (M+H)⁺=310.0. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.22-7.31 (2H, m), 7.13 (2H, d, J=8.55 Hz), 4.46-4.64 (1H,m), 4.43 (1H, br. s.), 3.97-4.14 (1H, m), 3.91 (1H, d, J=3.36 Hz), 3.09(3H, d, J=4.88 Hz).

Preparation Kc2-chloro-8-(4-chlorophenyl)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation K) (500 mg, 1.584 mmol) and Dimethylamine (2.0 M in THF)(1.188 mL, 2.377 mmol) were combined an purified as per Preparation Hato give2-chloro-8-(4-chlorophenyl)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(400 mg, 1.234 mmol, 78% yield) as a white solid. LC-MS (M+H)⁺=324.0. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.20-7.31 (2H, m), 7.04-7.15 (2H, m),4.70-4.89 (2H, m), 4.17 (1H, dd, J=11.60, 5.49 Hz), 4.05 (1H, t, J=5.49Hz), 3.87 (1H, dd, J=11.60, 5.49 Hz), 3.05-3.19 (6H, m).

Preparation L2,4-dichloro-8-(4-bromophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

The title compound was prepared in the analogous fashion to PreparationJ, as a pale yellow solid. LC-MS (M+H)⁺=359.0. ¹H NMR (400 MHz, CD₃OD) δppm 7.52 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 4.87 (1H, d, J=16.0Hz), 4.30 (1H, t, J=4.6 Hz), 4.14 (1H, dd, J=4.6, 11.4 Hz), 3.95 (1H,dd, J=4.8, 11.6 Hz).

Preparation La8-(4-bromophenyl)-2-chloro-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

8-(4-bromophenyl)-2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation L) (500 mg, 1.389 mmol) and methanamine hydrochloride (141mg, 2.083 mmol) were combined and purified as per Preparation Ha to give8-(4-bromophenyl)-2-chloro-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(210 mg, 0.592 mmol, 42.6% yield). LC-MS (M+H)⁺=356.0. ¹H NMR (500 MHz,MeOD) δ ppm 7.46 (2H, d, J=8.24 Hz), 7.13 (2H, d, J=8.55 Hz), 4.43-4.71(2H, m), 4.09 (1H, dd, J=11.44, 4.12 Hz), 3.92-4.03 (1H, m), 3.86 (1H,d, J=3.05 Hz), 3.00 (3H, s).

Preparation M2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine

Intermediate M(1)

ethyl 2-hydroxy-2-phenylacetate

A solution of pyrimidine-2,4,6-triol (10.0 g, 78.2 mmol), DMF (12 mL) inPOCl₃ (10 vol.) was heated at reflux for 15 h. The excess of POCl₃ wasevaporated under reduced pressure. The residue was poured in to crushedice. The precipitated solid was filtered and washed with water to give2,4,6-trichloropyrimidine-5-carbaldehyde (8.0 g, 47%) as yellow solid.This compound was taken to the next step without further purification.

Intermediate M(2)

2,4,6-trichloro-5-(1,3-dioxolan-2-yl)pyrimidine

To a solution of Intermediate M(1) (5.0 g, 23.6 mmol) in dry benzene wasadded ethylene glycol (4.0 mL, 64.5 mmol) followed by p-toluenesulfonicacid (0.15 g, 0.87 mmol) at room temperature. The reaction mixture washeated at reflux for 20 h. The reaction mixture was filtered and washedwith warm benzene. The filtrate was evaporated under reduced pressureand the residue was purified by column chromatography (Silica gel,60-120 mesh) using 10% ethyl acetate in pet-ether as mobile phase togive (4.5 g, 75%) as off-white solid. LC-MS (M+H)⁺=256.0. ¹H NMR (400MHz, DMSO-d6): δ ppm 9.6 (1H, s), 7.99 (1H, s), 7.98 (1H, s), 7.76-7.41(3H, m), 7.23-7.13 (4H, m), 5.87 (1H, s), 5.33 (1H, dd, J=27, 8 Hz),5.17 (1H, dd, J=27, 8), 4.67 (4H, m), 3.72 (3H, s).

Intermediate M(3)

2,4-dichloro-5-(1,3-dioxolan-2-yl)-6-(4-fluorobenzyl)pyrimidine

To a solution of Intermediate M(2) (4.0 g, 15.6 mmol) in dry diethylether was added 4-fluorobenzyl magnesium bromide (75.2 mL, 18.8 mmol,0.25 M solution in THF) at 0° C. The reaction mixture was allowed tocome to room temperature and stirred for 4 h. The reaction mixture wasquenched with aqueous saturated ammonium chloride. The organic layer wasseparated and the aqueous layer was extracted with diethyl ether (50mL×2). The combined organic layer was washed with water, dried overanhydrous Na₂SO₄ and evaporated to get crude compound. The crudecompound was purified by combiflash using 1.4% ethyl acetate in petether as mobile phase to give2,4-dichloro-5-(1,3-dioxolan-2-yl)-6-(4-fluorobenzyl)pyrimidine (2.2 g,43.1%) as off-white solid. LC-MS (M−H)⁺=327.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 7.26 (2H, m), 7.10 (2H, m), 6.19 (1H, s), 4.25 (2H, s),4.19 (2H, m), 4.02 (2H, m).

Intermediate M(4)

(2,4-dichloro-6-(4-fluorobenzyl)pyrimidin-5-yl)methanol

To a solution of Intermediate M(3) (2.0 g, 6.07 mmol) in THF was addedaqueous 6 N HCl over a period of 5 min. at room temperature. Thereaction mixture was heated at reflux for 1 h. The reaction volume wasreduced to half and the solution was extracted with diethyl ether (50mL×2). The combined organic layer was washed with water (50 mL), brinesolution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound (1.2 g). The crude compound wasdissolved in methanol and cooled to 0° C. Sodium borohydride (0.234 g)was added to the reaction mixture. The resulting solution was allowed tocome to room temperature and stirred for 1 h. The reaction mixture wasquenched with aqueous saturated ammonium chloride, and then solvent wasevaporated under reduced pressure. The residue was diluted with ethylacetate (50 mL). The organic solution was washed with water (25 mL),brine solution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (Silica gel, 60-120 mesh) using 20% ethylacetate in pet ether as mobile phase to give(2,4-dichloro-6-(4-fluorobenzyl)pyrimidin-5-yl)methanol (1.0 g, 58%) asoily liquid. LC-MS (M+H)⁺=488.1. ¹H NMR (300 MHz, CDCl₃): δ ppm 7.25(2H, m), 7.01 (2H, m), 4.82 (2H, m), 4.27 (2H, s).

Preparation M2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine

To a solution of Intermediate M(4) (1.0 g, 3.48 mmol) in dry benzene(100 mL) was added Cs₂CO₃ (0.4 g, 3.48 mmol) followed by lead tetraacetate (0.3 g, 3.48 mmol) at room temperature (the color of thereaction mixture was changed from colorless to brown). The reaction masswas heated at reflux for 18 h using Dean Stark apparatus. The reactionmixture was filtered through celite bed and washed with diethyl ether.The filtrate was evaporated under reduced pressure and the residue wasdiluted with diethyl ether. The organic solution was washed with water(25 mL×2), aqueous saturated NaHCO₃, brine solution (10 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to get crudecompound. The crude compound was purified by Combiflash using 0.9% ethylacetate in pet-ether as mobile phase to give2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (0.250mg, 30%) as oily liquid. LC-MS (M+H)⁺=485.0. ¹H NMR (400 MHz,methanol-d4): δ ppm 7.48-7.44 (2H, m), 7.16-7.12 (2H, m), 6.15 (1H, s),5.40 (1H, dd, J=13.6 Hz), 5.27 (1H, dd, J=13.6).

Preparation Ma2-chloro-7-(4-fluorophenyl)-N-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine

2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation M) (250 mg, 0.877 mmol) and methanamine hydrochloride (89mg, 1.315 mmol) were combined and purified as per Preparation Ia to give2-chloro-7-(4-fluorophenyl)-N-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine(149 mg, 0.533 mmol, 60.8% yield). LC-MS (M+H)⁺=280.0. ¹H NMR (500 MHz,MeOD) δ ppm 7.31-7.44 (2H, m), 7.05-7.17 (2H, m), 5.80-5.95 (1H, m),4.94-5.21 (2H, m), 2.93-3.07 (3H, m).

Preparation Mb2-chloro-N-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine

2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation M) (125 mg, 0.438 mmol) and ethylamine hydrochloride (53.6mg, 0.658 mmol) were combined and purified as per Preparation Ha to give2-chloro-N-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine(38.17 mg, 0.130 mmol, 29.6% yield). LC-MS (M+H)⁺=294.0. ¹H NMR (500MHz, CDCl₃) δ ppm 7.24-7.38 (2H, m), 6.92-7.08 (2H, m), 5.73-5.98 (1H,m), 4.83-5.21 (2H, m), 3.36-3.63 (2H, m), 1.13-1.28 (3H, m).

Preparations Mc1 and Mc22-chloro-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine

2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation M) (125 mg, 0.438 mmol) and (S)-3-fluoropyrrolidine, HCl(83 mg, 0.658 mmol) were combined and purified as per Preparation Ha togive2-chloro-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine

(Mc1, Diastereomer 1, first to elute) (49 mg, 0.145 mmol, 33.1% yield).LC-MS (M+H)⁺=338.0.

(Mc2, Diastereomer 2, second to elute) (40 mg, 0.118 mmol, 27.0% yield).

LC-MS (M+H)⁺=338.0. The relative stereochemistry of Mc1 and Mc2 was notdetermined

Preparation Md2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine

To a solution of Preparation M (0.05 g, 0.176 mmol) in methanol wasadded diisopropylethylamine (0.045 g, 0.30 mmol) followed by addition of3,3-difluoroazitidine hydrochloride (0.03 g, 0.193 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 18h. The solvent was removed under reduced pressure and the residue waspurified by column chromatography (60-120 mesh) using 6% ethyl acetatein pet-ether as mobile phase to give2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine(0.035 g, 46%) as white solid. LC-MS (M+H)⁺=342.2.

Preparation Me2-chloro-7-(4-fluorophenyl)-4-((S)-2-methylpyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine

2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation M) was reacted as described in Preparation Hp1 and Hp2 with(S)-2-methylpyrrolidine p-toluenesulfonate salt to afford2-chloro-7-(4-fluorophenyl)-4-((S)-2-methylpyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation Me) as a mixture of 2 diasteriomers. LC-MS (M+H)⁺=334.1.

Preparation Mf2-chloro-N—((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation M) (150 mg, 0.526 mmol) in THF (2631 μL) was added(R)-1-cyclopropylethanamine, HCl (128 mg, 1.052 mmol) and DIEA (368 μL,2.105 mmol). The mixture was heated at 40° C. for 2 h and stirred at RTovernight. The mixture was concentrated and purified by columnchromatography on silica gel to give2-chloro-N—((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine(Preparation Mf) (25 mg, 0.075 mmol, 14.24% yield) as a mixture of 2diasteriomers. LC-MS (M+H)⁺=334.1.

Preparation Mg

2-chloro-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine

2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation M) was reacted as described in Preparation Xa with(R)-3-fluoropyrrolidine, HCl to give2-chloro-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation Mg). LC-MS (M+H)⁺=338.1. ¹H NMR (400 MHz, CDCl₃) δ ppm7.33-7.47 (m, 2H) 7.00-7.14 (m, 2H) 5.83-5.97 (m, 1H) 5.54 (dd, J=11.33,3.53 Hz, 1H) 5.36-5.49 (m, 2H) 3.88-4.00 (m, 1H) 3.65-3.88 (m, 3H)2.30-2.52 (m, 1H) 2.02-2.20 (m, 1H).

Preparation Mh2-chloro-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine

2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation M) was reacted as described in Preparation Xa with(2R,6S)-2,6-dimethylmorpholine to give2-chloro-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation Mh). LC-MS (M+H)⁺=364.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.39(dd, J=8.70, 5.34 Hz, 2H) 7.07 (t, J=8.70 Hz, 2H) 5.90 (br. s., 1H)5.34-5.42 (m, 1H) 5.24-5.34 (m, 1H) 4.14 (q, J=7.02 Hz, 2H) 3.67 (ddd,J=10.38, 6.41, 2.44 Hz, 4H), 1.20 (m, 6H).

Preparation N2,4-dichloro-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine

Intermediate N(1)

ethyl 2-hydroxy-2-phenylacetate

To a cooled solution of ethyl 2-hydroxy-2-phenylacetate (25.0 g, 164.3mmol) in ethanol was added con. H₂SO₄ (15 mL) over a period of 10 min.The reaction mixture was heated at reflux for 5 h. The solvent wasevaporated under reduced pressure and the residue was diluted with ethylacetate (250 mL). The organic solution was washed with aqueous saturatedNaHCO₃ (200 mL×2), water (100 mL×2), brine solution (100 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to give ethyl2-hydroxy-2-phenylacetate (24.5 g, 83%) as crude compound (oily liquid).The crude compound was taken to the next step without furtherpurification. LC-MS (M+H₂O)⁺=198.2. ¹H NMR (400 MHz, DMSO-d6): δ ppm7.41-7.28 (5H, m), 6.04 (1H, d, J=4.0 Hz), 5.11 (1H, d, J=4.0 Hz), 4.13(2H, m), 1.13 (3H, t, J=7.2 Hz).

Intermediate N(2)

ethyl 4-(2-ethoxy-2-oxo-1-phenylethoxy)but-2-enoate

To a solution of Intermediate N(1) (20.0 g, 110.9 mmol) in hexane wasadded silver oxide (66.75 g, 288.5 mmol) followed by magnesium sulphate(2.66 g, 220 mmol) at room temperature. The reaction mixture was heatedat reflux for 1 h. The reaction mixture was cooled to 0° C. and wasadded silver oxide (71.8 g, 310.9 mmol) followed byethyl-4-bromochrotonate (32.0 g, 166 mmol). The resulting solution wasstirred at room temperature for 3 days. The reaction mass was filteredthrough a bed of diatomaceous earth (Celite®) and washed with ethylacetate. The filtrate was evaporated under reduced pressure to giveethyl 4-(2-ethoxy-2-oxo-1-phenylethoxy)but-2-enoate (20.0 g, 62.5%) asoily liquid. LC-MS (M+H₂O)⁺=310.2. ¹H NMR (400 MHz, DMSO-d6): δ ppm7.42-7.35 (5H, m), 6.90 (1H, m), 6.05 (1H, m), 5.09 (1H, s), 4.26 (2H,m), 4.16 (4H, m), 1.21 (3H, t, J=7.2 Hz), 1.13 (3H, t, J=7.2 Hz).

Intermediate N(3)

ethyl 4-(2-ethoxy-2-oxo-1-phenylethoxy)butanoate

To a solution of Intermediate N(2) (20.0 g, 68.41 mmol) in ethanol wasadded palladium on carbon (10%, w/w) at room temperature. The reactionmixture was hydrogenated under balloon pressure of hydrogen for 30 h.The reaction mass was filtered through a bed of diatomaceous earth(Celite®) and washed with ethanol. The solvent was removed under reducedpressure and the residue was purified by column chromatography (Silicagel, 60-120 mesh) using 5% ethyl acetate in petroleum-ether as mobilephase to give ethyl 4-(2-ethoxy-2-oxo-1-phenylethoxy)butanoate (12.0 g,59.5%) as oily liquid. LC-MS (M+H)⁺=295.2. ¹H NMR (400 MHz, DMSO-d6): δppm 7.41-7.27 (5H, m), 4.96 (1H, s), 4.07 (4H, m), 3.62 (1H, m), 3.49(1H, m), 2.36 (2H, m), 1.79 (2H, m), 1.15 (6H, m).

Intermediate N(4)

ethyl 3-oxo-2-phenyltetrahydro-2H-pyran-4-carboxylate

To a cooled solution of Intermediate N(3) (12.0 g, 40.76 mmol) in THFwas added t-BuOK (9.13 g, 81.3 mmol) at 0° C. The reaction mixture wasallowed to come to room temperature and stirred for 1 h. The reactionmixture was quenched with water and evaporated the solvent under reducedpressure. The residue was diluted with ethyl acetate (200 mL). Theorganic layer was washed with water (100 mL×2), brine solution (100 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 50% ethyl acetate in pet-ether as mobilephase to give ethyl 3-oxo-2-phenyltetrahydro-2H-pyran-4-carboxylate (6.0g, 59.4%) as oily liquid. LC-MS (M+H)⁺=249.2. ¹H NMR (400 MHz, DMSO-d6):δ ppm 11.81 (1H, s), 7.36 (5H, m), 5.20 (1H, s), 4.23 (2H, q, J=7.2.0Hz), 3.71 (1H, m), 3.67 (1H, m), 2.36 (1H, m), 2.32 (1H, m), 1.29 (3H,t, J=7.2 Hz).

Intermediate N(5)

8-phenyl-5,6-dihydro-1H-pyrano[3,4-d]pyrimidine-2,4(3H,8H)-dione

To a solution of Intermediate N(4) (6.0 g, 24.16 mmol) in ethanol wasadded t-BuOK (6.76 g, 60.41 mmol) followed by urea (3.62 g, 60.41 mmol)at room temperature. The reaction mass was heated at reflux for 18 h.The reaction mixture was quenched with water and evaporated the solventunder reduced pressure. The residue was diluted with ethyl acetate (100mL). The organic layer was washed with water (100 mL×2), brine solution(100 mL), dried over anhydrous Na₂SO₄ and evaporated under reducedpressure to get crude compound. The crude compound was purified bycolumn chromatography (Silica gel, 60-120 mesh) using ethyl acetate asmobile phase to give8-phenyl-5,6-dihydro-1H-pyrano[3,4-d]pyrimidine-2,4(3H,8H)-dione (3.0 g,50.8%) as pale yellow solid. LC-MS (M−H)⁺=243.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 11.10 (1H, s), 10.57 (1H, s), 7.42-7.39 (3H, m), 7.32(2H, m), 5.32 (1H, s), 3.71-3.56 (2H, m), 2.38-2.27 (2H, m).

Preparation N2,4-dichloro-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine

A solution of Intermediate N(5) (2.0 g, 8.18 mmol) and catalytic amountof DMF in POCl₃ (10 vol.) was heated at reflux for 18 h. The excess ofPOCl₃ was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 min. The aqueous solution wasextracted with ethyl acetate (50 mL×3). The combined organic layer waswashed with aqueous saturated NaHCO₃ (50 mL×2), brine solution (50 mL),dried over Na₂SO₄ and evaporated under reduced pressure to give2,4-dichloro-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine (2.0 g,crude) as brown solid. LC-MS (M+H)⁺=281.0.

Preparation Na2-chloro-N-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine

To a solution of Preparation N (2.1 g, crude) in acetonitrile was addeddiisopropylethylamine (1.83 g, 14.2 mmol) followed by addition ofmethylamine hydrochloride (0.96 g, 14.2 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified bycolumn chromatography (60-120 mesh) using 40% ethyl acetate in pet-etheras mobile phase to give2-chloro-N-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine(0.7 g, 35.7%) as off-white solid. LC-MS (M+H)⁺=276.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 7.49 (1H, m), 7.36-7.31 (3H, m), 7.25-7.23 (2H, m), 5.45(1H, s), 4.0 (1H, m), 3.79 (1H, m), 2.87 (3H, d, J=4.4 Hz), 2.55 (1H,m), 2.44 (1H, m).

Preparation O2,4-dichloro-8-(4-fluorophenyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine

Intermediate O(1)

ethyl 2-(4-fluorophenyl)-2-hydroxyacetate

To a cooled solution of 2-(4-fluorophenyl)-2-hydroxyacetic acid (5.0 g,29.4 mmol) in ethanol was added con. H₂SO₄ (10 mL) over a period of 10min. The reaction mixture was heated at reflux for 5 h. The solvent wasevaporated under reduced pressure and the residue was diluted with ethylacetate (25 mL). The organic solution was washed with aqueous saturatedNaHCO₃ (25 mL×2), water (20 mL), brine solution (10 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to give ethyl2-(4-fluorophenyl)-2-hydroxyacetate (5.0 g, 90%) as crude compound (oilyliquid). The crude compound was taken to the next step without furtherpurification. LC-MS (M+H₂O)⁺=216. ¹H NMR (400 MHz, DMSO-d6): δ 7.43-7.46(2H, m), 7.17-7.20 (2H, m), 6.11-6.13 (1H, m), 5.14 (1H, d, J=5.20 Hz),3.35-4.13 (2H, m), 1.12-1.15 (3H, m).

Intermediate O(2)

ethyl 4-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethoxy)but-2-enoate

To a solution of Intermediate O(1) (3.0 g, 15.1 mmol) in hexane wasadded silver oxide (9.1 g, 39.3 mmol) followed by magnesium sulphate(1.8 g, 3.0 mmol) at room temperature. The reaction mixture was heatedat reflux for 1 h. The reaction mixture was cooled to 0° C. and wasadded silver oxide (9.7 g, 39.9 mmol) followed byethyl-4-bromochrotonate (4.3 g, 22.7 mmol). The resulting solution wasstirred at room temperature for 3 days. The reaction mass was filteredthrough a bed of diatomaceous earth (Celite®) and washed with ethylacetate. The filtrate was evaporated under reduced pressure to giveethyl 4-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethoxy)but-2-enoate (3.0 g,90%) as oily liquid. LC-MS (M+H₂O)⁺=328.2. ¹H NMR (400 MHz, CDCl₃): δppm 7.42-7.45 (2H, m), 7.04-7.26 (2H, m), 6.95 (1H, m), 6.12 (1H, m),4.89 (1H, s), 4.13-4.28 (6H, m), 1.30 (3H, t, J=7.20 Hz), 1.26 (3H,J=6.8 Hz).

Intermediate O(3)

ethyl 4-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethoxy)butanoate

To a solution of Intermediate O(2) (3.0 g, 9.6 mmol) in ethanol wasadded palladium on carbon (10%, w/w) at room temperature. The reactionmixture was hydrogenated under balloon pressure of hydrogen for 30 h.The reaction mass was filtered through a bed of diatomaceous earth(Celite®) and washed with ethanol. The solvent was removed under reducedpressure and the residue was purified by column chromatography (Silicagel, 60-120 mesh) using 5% ethyl acetate in pet-ether as mobile phase togive ethyl 4-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethoxy)butanoate (3.0 g,63%) as oily liquid. LC-MS (M+H)⁺=313.2 ¹H NMR (400 MHz, CDCl₃): δ ppm7.29-7.46 (2H, m), 7.05-7.09 (2H, m), 4.84 (1H, s), 4.10-4.23 (4H, m),3.59-3.63 (1H, m), 3.42-3.53 (1H, m), 2.47 (2H, t, J=7.6 Hz), 1.99 (2H,t, J=7.6 Hz), 1.22-1.32 (6H, m).

Intermediate O(4)

ethyl 2-(4-fluorophenyl)-3-oxotetrahydro-2H-pyran-4-carboxylate

To a cooled solution of Intermediate O(3) (3.0 g, 9.6 mmol) in THF wasadded t-BuOK (2.1 g, 19.0 mmol) at 0° C. The reaction mixture wasallowed to come to room temperature and stirred for 1 h. The reactionmixture was quenched with water and evaporated the solvent under reducedpressure. The residue was diluted with ethyl acetate (200 mL). Theorganic layer was washed with water (100 mL×2), brine solution (100 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 50% ethyl acetate in petroleum-ether asmobile phase to give ethyl2-(4-fluorophenyl)-3-oxotetrahydro-2H-pyran-4-carboxylate (1.0 g, 55%)as oily liquid. LC-MS (M+H)⁺=267.1. ¹H NMR (400 MHz, DMSO-d6): δ ppm11.81 (1H, s), 7.22-7.42 (2H, m), 7.12-7.20 (2H, m), 5.23 (1H, s), 4.22(2H, q, J=7.2 Hz), 3.87-3.88 (1H, m), 3.69-3.84 (1H, m), 2.34-2.35 (1H,m), 2.30-2.33 (1H, m), 1.27 (3H, t, J=7.2 Hz).

Intermediate O(5)

8-(4-fluorophenyl)-5,6-dihydro-1H-pyrano[3,4-d]pyrimidine-2,4(3H,8H)-dione

To a solution of Intermediate O(4) (0.30 g, 1.12 mmol) in ethanol wasadded t-BuOK (0.253 g, 2.2 mmol) followed by urea (0.135 g, 2.2 mmol) atroom temperature. The reaction mass was heated at reflux for 18 h. Thereaction mixture was quenched with water and evaporated the solventunder reduced pressure. The residue was diluted with ethyl acetate (100mL). The organic layer was washed with water (100 mL×2), brine solution(100 mL), dried over anhydrous Na₂SO₄ and evaporated under reducedpressure to get crude compound. The crude compound was purified bycolumn chromatography (Silica gel, 60-120 mesh) using ethyl acetate asmobile phase to give8-(4-fluorophenyl)-5,6-dihydro-1H-pyrano[3,4-d]pyrimidine-2,4(3H,8H)-dione(0.150 g, 40%) as pale yellow solid. LC-MS (M−H)⁺=263.1. ¹H NMR (400MHz, DMSO-d6): δ ppm 11.14 (1H, s), 10.57 (1H, s), 7.35-7.36 (2H, m),7.22 (2H, m), 5.34 (1H, s), 3.66-3.71 (1H, m), 3.58-3.64 (1H, m), 2.33(2H, m).

Preparation O2,4-dichloro-8-(4-fluorophenyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine

A solution of Intermediate O(5) (0.30 g, 1.1 mmol) and catalytic amountof DMF in POCl₃ (10 vol.) was heated at reflux for 18 h. The excess ofPOCl₃ was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 min. The aqueous solution wasextracted with ethyl acetate (50 mL×3). The combined organic layer waswashed with aqueous saturated NaHCO₃ (50 mL×2), brine solution (50 mL),dried over Na₂SO₄ and evaporated under reduced pressure to give2,4-dichloro-8-(4-fluorophenyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine(0.20 g, crude) as brown liquid. LC-MS (M+H)⁺=299.0.

Preparation Oa2-chloro-N-ethyl-8-(4-fluorophenyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine

To a solution of Preparation O (0.35 g, 1.1 mmol) in methanol was addeddiisopropylethylamine (0.30 g, 2.2 mmol) followed by addition ofethylamine hydrochloride (0.113 g, 1.1 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified bycolumn chromatography (60-120 mesh) using 35% ethyl acetate in pet-etheras mobile phase to give2-chloro-N-ethyl-8-(4-fluorophenyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine(0.15 g, crude) as off-white solid. LC-MS (M+H)⁺=308.2.0.

Preparation Ob2-chloro-N-ethyl-8-(4-fluorophenyl)-N-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine

To a solution of Preparation O (0.20 g, 0.61 mmol) in methanol was addeddiisopropylethylamine (0.172 g, 1.3 mmol) followed by addition ofethylmethylamine hydrochloride (0.47 g, 0.81 mmol) at room temperature.The reaction mixture was stirred at room temperature for 18 h. Thesolvent was removed under reduced pressure and the residue was purifiedby column chromatography (60-120 mesh) using 40% ethyl acetate inpet-ether as mobile phase to give2-chloro-N-ethyl-8-(4-fluorophenyl)-N-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine(0.020 g crude) as off-white solid. LC-MS (M+H)⁺=322.2.

Preparation Oc1 and Oc22-chloro-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine

To a solution of Preparation O (0.60 g, 2.1 mmol) in methanol was addeddiisopropylethylamine (0.516 g, 4.6 mmol) followed by addition of(R)-3-fluoropyrrolidine (0.301 g, 2.2 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified bypep-HPLC to give2-chloro-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine(0.110 g, 40% Isomer 1, 0.109 g, 40% Isomer 2) as off-white solid. LC-MS(M+H)⁺=352.0.

Oc1: ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.36-7.36 (2H, m), 7.16 (2H, m),5.50 (2H, d, J=8.40 Hz), 5.35 (1H, s), 3.58-3.98 (7H, m), 3.24-3.34 (1H,m), 2.78 (1H, m), 2.04-2.28 (2H, m).

Oc2: ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.19-7.33 (2H, m), 7.15-7.20 (2H,m), 5.34 (1H, m), 5.40 (1H, m), 3.91-4.10 (2H, m), 3.75-3.90 (2H, m),3.69-3.75 (2H, m), 3.05 (2H, t, J=5.20 Hz), 2.01 (2H, d, J=8.0 Hz).

Preparation Od1 and Od22-chloro-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine

To a solution of Preparation O (0.60 g, 2.1 mmol) in methanol was addeddiisopropylethylamine (0.516 g, 4.6 mmol) followed by addition of(S)-3-fluoropyrrolidine (0.301 g, 2.2 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified bypep-HPLC to give2-chloro-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine(0.102 g, 39% Isomer 1, 0.111 g, 40% Isomer 2) as off-white solid. LC-MS(M+H)⁺=352.0.

Od1: ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.36-7.36 (2H, m), 7.16 (2H, m),5.50 (2H, d, J=8.4 Hz), 5.35 (1H, s), 3.58-3.98 (7H, m), 3.24-3.34 (1H,m), 2.78 (1H, d, J=8.4 Hz), 2.04-2.28 (2H, m).

Od2: ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.19-7.33 (2H, m), 7.15-7.20 (2H,m), 5.34 (1H, m), 5.40 ((1H, m), 3.91-4.10 (2H, m), 3.75-3.90 (2H, m),3.69-3.75 (m, 2H), 3.05 (2H, t, J=5.20 Hz), 2.01 (2H, d, J=8.0 Hz).

Preparation P2,4-Dichloro-7-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Intermediate P(1)

1-Chloro-4-cyclopentenylbenzene

To a 1 M solution of 4-chlorophenyl)magnesium bromide (149 mL, 149 mmol)was added cyclopentanone (13.23 mL, 149 mmol). The solution turned warmupon the addition. The reaction mixture was stirred at reflux for 2 h.The reaction mixture was cooled to room temperature and quenched with 10g of ice. 6N hydrochloric acid solution was added until the precipitatedissolved completely. Ether was added. The organic layer was separatedand the aqueous phase was extracted with ether. The combined organicextracts were washed with saturated aqueous solution of sodium hydrogensulfite, saturated aqueous solution of sodium bicarbonate and water. Theorganic layer was dried over anhydrous magnesium sulfate and filtered.The solvent was removed in vacuum and the residue was purified by columnchromatography on silica gel to give 1-chloro-4-cyclopentenylbenzene(20.0 g, 112 mmol, 75% yield) as a colorless oil. LC-MS (M+H)⁺=179.2. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.27-7.39 (4H, m), 6.19 (1H, s), 2.66-2.74(2H, m), 2.52-2.61 (2H, m), 2.01-2.12 (2H, m).

Intermediate P(2)

2-(4-Chlorophenyl)cyclopentanone

A mixture of formic acid (60 mL, 84 mmol) and hydrogen peroxide (15 mL,84 mmol) was warmed at 40° C. for 10 min. The resulting solution wascarefully added to 1-chloro-4-cyclopentenylbenzene (15 g, 84 mmol) understirring. The two-phase system was initially stirred at roomtemperature. After a certain period of time, a spontaneous exothermicreaction took place, and the temperature rose to about 50° C. Thereaction mixture was stirred at room temperature for 1 h. The LC/MSanalysis of the reaction mixture shows the disappearance of the startingmaterial and the formation of the product. The reaction mixture wasquenched by careful addition of a saturated sodium bicarbonate solution.Ether was added and the reaction mixture was vigorously shaken. Theorganic layer was separated and the aqueous layer was extracted withether. The combined organic extracts were dried over anhydrous magnesiumsulfate and filtered. The solvent was removed in vacuum and the residuewas purified by column chromatography on silica gel to give2-(4-chlorophenyl)cyclopentanone (5.7 g, 29.3 mmol, 34.9% yield) as acolorless oil. LC-MS (M+H)⁺=195.2. ¹H NMR (500 MHz, CDCl₃) δ ppm7.21-7.37 (2H, m), 7.11 (2H, d, J=8.5 Hz), 3.25 (1H, dd, J=11.6, 8.5Hz), 2.44 (2H, d, J=6.1 Hz), 2.15-2.31 (1H, m), 1.96-2.15 (3H, m),1.78-1.95 (1H, m).

Intermediate P(3)

7-(4-Chlorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione

A solution of 2-(4-chlorophenyl)cyclopentanone (7.80 g, 40.1 mmol) andcarbonisocyanatidic chloride (7.61 g, 72.1 mmol) was stirred at 58° C.in a high-pressure vessel for 1 h. The temperature was raised to 130° C.and the reaction mixture was stirred for an additional 2 h. Aftercooling to rt, the reaction mixture solidified. The solid residue wasdissolved in ethyl acetate and washed with saturated aqueous solution ofsodium bicarbonate. The organic layer was separated and the aqueouslayer was extracted twice with ethyl acetate. The combined organicextracts were dried over anhydrous sodium sulfate and filtered. Thesolvent was removed in vacuum and the oily residue was purified bycolumn chromatography on silica gel to provide7-(4-chlorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(5.4 g, 20.48 mmol, 51.1% yield). LC-MS (M+H)⁺=264.2. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.32 (2H, d, J=8.5 Hz), 7.12 (2H, d, J=8.5 Hz), 4.15-4.25(1H, m), 2.56-2.93 (4H, m).

Intermediate P(4)

7-(4-Chlorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

A solution of7-(4-chlorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(5.4 g, 20.48 mmol) in concentrated ammonium hydroxide (59.8 mL, 1536mmol) was stirred at 100° C. in a high-pressure vessel for 6 h. Theformation of white precipitate was observed during the heating. Thesolvent was removed in vacuum to provide7-(4-chlorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(4.9 g, 18.65 mmol, 91% yield) as a off-white solid. LC-MS (M+H)⁺=263.2.¹H NMR (500 MHz, DMSO-d6) δ ppm 7.37 (2H, d, J=8.2 Hz), 7.19 (1H, d,J=8.5 Hz), 4.16 (1H, d, J=5.2 Hz), 3.79 (1H, br s), 3.17 (1H, s), 2.51(2H, d, J=1.8 Hz), 1.75-1.85 (1H, m).

Preparation P2,4-Dichloro-7-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A mixture of7-(4-chlorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(4.7 g, 17.89 mmol), POCl₃ (53.4 mL, 573 mmol) and N,N-dimethylaniline(18.26 mL, 143 mmol) was heated at 110° C. overnight. The reactionmixture was poured into a beaker with ice. The inside walls of thereaction vessel was washed with DCM. As soon as the ice completelymelted, the organic layer was separated and the aqueous layer wasextracted with DCM. The combined organic extracts were dried overanhydrous sodium sulfate and filtered. The solvent was removed in vacuumand the residue was purified by column chromatography on silica gel toprovide2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(1.2 g, 4.01 mmol, 22.39% yield). LC-MS (M+H)⁺=299.0. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.41-7.99 (2H, m), 7.09 (2H, d, J=8.5 Hz), 4.41 (1H, t,J=8.4 Hz), 2.94-3.18 (2H, m), 2.73 (1H, dt, J=8.9, 4.5 Hz), 2.15-2.33(1H, m).

Preparation Pa2-Chloro-7-(4-chlorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(200 mg, 0.668 mmol) and excess dimethylamine (3.34 mL, 6.68 mmol) inMeOH (4 mL) was stirred at rt for 30 min. The solvent was removed invacuum and the crude product was purified by column chromatography onsilica gel to afford2-chloro-7-(4-chlorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(98 mg, 0.318 mmol, 47.6% yield). LC-MS (M+H)⁺=308.1.

Preparation Pb2-Chloro-7-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(325 mg, 1.085 mmol), N-ethyl-N-isopropylpropan-2-amine (0.945 mL, 5.42mmol) and 3,3-difluoroazetidine, HCl salt (281 mg, 2.170 mmol) in MeOH(5 mL) was stirred at rt for 1 h. The solvent was removed in vacuum andthe crude product was purified by column chromatography on silica gel toafford2-chloro-7-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(70 mg, 0.197 mmol, 18.12% yield). LC-MS (M+H)⁺=356.1.

Preparation Pc2-Chloro-7-(4-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(300 mg, 1.001 mmol), methanamine, HCl salt (135 mg, 2.003 mmol) andDIPEA (0.700 mL, 4.01 mmol) in MeOH (6 mL) was stirred at rt for 30 min.The solvent was removed in vacuum and the crude product was purified bycolumn chromatography on silica gel to afford2-chloro-7-(4-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(101 mg, 0.343 mmol, 34.3% yield). LC-MS (M+H)⁺=294.2.

Preparation Q2,4-Dichloro-7-(3,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Intermediate Q(1)

7-(3,4-Difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione

A solution of 2-(3,4-difluorophenyl)cyclopentanone, (prepared in themanner of Intermediate P(1) and P(2)) (1.5 g, 7.65 mmol) andcarbonisocyanatidic chloride (1.129 g, 10.70 mmol) was stirred at 58° C.in a high-pressure vessel for 1 h. The temperature was raised to 130° C.and the reaction mixture was stirred for an additional 2 h. Aftercooling to rt, the reaction mixture solidified. The solid residue wasdissolved in ethyl acetate and washed with saturated aqueous solution ofsodium bicarbonate. The organic layer was separated and the aqueouslayer was extracted twice with ethyl acetate. The combined organicextracts were dried over anhydrous sodium sulfate and filtered. Thesolvent was removed in vacuum and the oily residue was purified bycolumn chromatography on silica gel to provide7-(3,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(1.05 g, 3.96 mmol, 51.8% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.16 (1H, br s), 7.15 (1H, dt, J=10.0, 8.3Hz), 6.97-7.05 (1H, m), 6.88-6.95 (1H, m), 2.80-2.90 (1H, m), 2.61-2.78(2H, m), 0.78-0.86 (2H, m).

Intermediate Q(2)

7-(3,4-Difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

A solution of7-(3,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(1.05 g, 3.96 mmol) in concentrated ammonium hydroxide (0.154 mL, 3.96mmol) was stirred at 100° C. in a high-pressure vessel (75 mL) for 6 h.The formation of white precipitate was observed during the heating. Thesolvent was removed in vacuum to provide7-(3,4-difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(1.046 g, 3.96 mmol, 100% yield) as a off-white solid. LC-MS(M+H)⁺=265.2.

Preparation Q2,4-Dichloro-7-(3,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A mixture of7-(3,4-difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(500 mg, 1.892 mmol), POCl₃ (5644 μL, 60.6 mmol) and N,N-dimethylaniline(1931 μL, 15.14 mmol) was heated at 120° C. overnight. The reactionmixture was poured into a beaker with ice. The inside walls of thereaction vessel was washed with DCM. As soon as the ice completelymelted, the content of the beaker was placed into a separatory funnel.The organic layer was separated and the aqueous layer was extracted withDCM. The combined organic extracts were dried over anhydrous sodiumsulfate and filtered. The solvent was removed in vacuum and the residuewas purified by column chromatography on silica gel to provide2,4-dichloro-7-(3,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(446 mg, 1.481 mmol, 78% yield). LC-MS (M+H)⁺=301.1.

Preparation Qa2-Chloro-7-(3,4-difluorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-(3,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(446 mg, 1.481 mmol) and excess dimethylamine (2.222 mL, 4.44 mmol) inMeOH (6 mL) was stirred at rt for 30 min. The solvent was removed invacuum and the crude product was purified by column chromatography onsilica gel to afford2-chloro-7-(3,4-difluorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(146 mg, 0.471 mmol, 31.8% yield). LC-MS (M+H)⁺=310.2.

Preparation Qb2-Chloro-7-(3,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-(3,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(421 mg, 1.398 mmol), methanamine, HCl (283 mg, 4.19 mmol) and DIPEA(1.465 mL, 8.39 mmol) in methanol (10 mL) was stirred at rt for 1 h. Thesolvent was removed in vacuum and the crude product was purified bycolumn chromatography on silica gel to afford2-chloro-7-(3,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(154 mg, 0.521 mmol, 37.2% yield). LC-MS (M+H)⁺=296.2.

Preparation R2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Intermediate R(1)

1-cyclopentenyl-4-(trifluoromethoxy)benzene

(4-(trifluoromethoxy)phenyl)magnesium bromide was reacted in the mannerof Intermediate P(1) to give1-cyclopentenyl-4-(trifluoromethoxy)benzene.

Intermediate R(2)

2-(4-(trifluoromethoxy)phenyl)cyclopentanone

1-cyclopentenyl-4-(trifluoromethoxy)benzene was reacted in the manner ofIntermediate P(2) to give 2-(4-(trifluoromethoxy)phenyl)cyclopentanone.

Intermediate R(3)

7-(4-(trifluoromethoxy)phenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione

2-(4-(trifluoromethoxy)phenyl)cyclopentanone was reacted in the mannerof Intermediate P(3) to provide7-(4-(trifluoromethoxy)phenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione.

Intermediate R(4)

7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

7-(4-(trifluoromethoxy)phenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dionewas reacted in the manner of Intermediate P(4) to provide7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione.

Preparation R2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dionewas reacted in the manner of Preparation P to provide2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidineas a pink solid. LC-MS (M+H)⁺=349.2. ¹H NMR (500 MHz, CD₃OD) δ ppm 7.31(2H, dd, J=2.0, 7.7 Hz), 7.25 (2H, d, J=7.4 Hz), 4.56 (1H, t, J=8.8 Hz),3.15 (1H, ddd, J=3.8, 9.1, 16.9 Hz), 3.09-3.00 (1H, m), 2.81-2.72 (1H,m), 2.27-2.22 (1H, m).

Preparation Ra2-Chloro-N-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(200 mg, 0.573 mmol), and methanamine (0.286 mL, 0.573 mmol) in MeOH (5mL) was stirred at rt for 1 h. The solvent was removed in vacuum toafford crude2-chloro-N-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(220 mg, 0.640 mmol, 112% yield). LC-MS (M+H)⁺=343.9.

Preparation Rb2-Chloro-N-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(200 mg, 0.573 mmol), and ethanamine (0.286 mL, 0.573 mmol) in MeOH (2mL) was stirred at rt for 1 h. The solvent was removed in vacuum and thecrude product was purified by column chromatography on silica gel toafford2-chloro-N-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(190 mg, 0.531 mmol, 93% yield). LC-MS (M+H)⁺=358.2.

Preparation Rc2-Chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(250 mg, 0.716 mmol), 3,3-difluoroazetidine, HCl salt (186 mg, 1.432mmol) and DIPEA (0.500 mL, 2.86 mmol) in MeOH (3 mL) was stirred at rtfor 1.5 h. The solvent was removed in vacuum and the crude product waspurified by column chromatography on silica gel to afford2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(244 mg, 0.601 mmol, 84% yield). LC-MS (M+H)⁺=406.0.

Preparation Rd2-Chloro-N,N-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(250 mg, 0.716 mmol) and dimethylamine (0.716 mL, 1.432 mmol) in MeOH (2mL) was stirred at rt for 1 h. The solvent was removed in vacuum and thecrude product was purified by column chromatography on silica gel toafford2-chloro-N,N-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(250 mg, 0.699 mmol, 98% yield). LC-MS (M+H)⁺=358.0.

Preparation Re4-(Azetidin-1-yl)-2-chloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(250 mg, 0.716 mmol) and azetidine (82 mg, 1.432 mmol) in MeOH (3 mL)was stirred at rt for 1 h. The solvent was removed in vacuum and thecrude product was purified by column chromatography on silica gel toafford4-(azetidin-1-yl)-2-chloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(238 mg, 0.644 mmol, 90% yield). LC-MS (M+H)⁺=371.2.

Preparation S2,4-Dichloro-7-(3,5-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Intermediate S(1)

(1S,2R)-2-(3,5-Difluorophenyl)cyclopentanol

A flask was charged with (3,5-difluorophenyl)magnesium bromide (149 mL,149 mmol) and copper (I) iodide (1.901 g, 9.98 mmol). To this reactionmixture, 6-oxabicyclo[3.1.0]hexane (12.53 g, 149 mmol) dissolved in THF(25 mL) was added dropwise. The reaction mixture warmed upon theaddition of the epoxide. The reaction was stirred at rt for 2 h at rt.The reaction mixture was quenched by the addition of a solution ofammonium chloride. Ether was added and the organic layer was collected,dried (Na₂SO₄) and concentrated. The crude product was purified bycolumn chromatography on silica gel to afford(1S,2R)-2-(3,5-difluorophenyl)cyclopentanol (26.5 g, 134 mmol, 90%yield).

¹H NMR (500 MHz, CDCl₃) δ ppm 6.72 (2H, dd, J=8.7, 2.0 Hz), 6.50-6.63(1H, m), 2.97 (1H, br s), 2.78 (1H, d, J=10.1 Hz), 1.96-2.15 (2H, m),1.66-1.85 (2H, m), 1.53-1.65 (2H, m).

Intermediate S(2)

2-(3,5-Difluorophenyl)cyclopentanone

To a solution of (1S,2R)-2-(3,5-difluorophenyl)cyclopentanol (6 g, 30.3mmol) in CH₂Cl₂ (150 mL) was added Dess-Martin periodinane (15.41 g,36.3 mmol). The reaction mixture was stirred at rt for 3 h. The reactionmixture was diluted with dichloromethane and quenched with the additionof 1 N NaOH. The organic layer was collected, dried (Na₂SO₄) andconcentrated. The crude product was purified by column chromatography onsilica gel to afford 2-(3,5-difluorophenyl)cyclopentanone (4.765 g,24.29 mmol, 80% yield). LC-MS (M+H)⁺=197.0. ¹H NMR (500 MHz, CDCl₃) δppm 6.70 (2H, d, J=6.7 Hz), 6.52-6.67 (1H, m), 3.17-3.33 (1H, m),2.33-2.56 (2H, m), 2.06-2.26 (2H, m), 2.01 (1H, dd, J=11.7, 6.3 Hz),1.89 (1H, br s).

Intermediate S(3)

7-(3,5-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione

A mixture of 2-(3,5-difluorophenyl)cyclopentanone (4.765 g, 24.29 mmol)and carbonisocyanatidic chloride (4.61 g, 43.7 mmol) was heated at 58°C. for 1 h and at 130° C. for 2 h. Upon cooling to room temperature, thereaction mixture was dissolved in ethyl acetate and washed withsaturated aqueous solution of sodium bicarbonate. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic extracts were dried over anhydrous magnesium sulfateand filtered. The solvent was removed in vacuum and the residue waspurified by column chromatography on silica gel to give7-(3,5-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(700 mg, 2.64 mmol, 10.87% yield). LC-MS (M+H)⁺=266.1. ¹H NMR (500 MHz,CDCl₃) δ ppm 8.79 (1H, br s), 6.68-6.86 (3H, m), 4.22 (1H, br s), 2.87(1H, dt, J=7.0, 4.4 Hz), 2.63-2.82 (2H, m), 2.15 (1H, br s).

Intermediate S(4)

7-(3,5-Difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

A solution of7-(3,5-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(700 mg, 2.64 mmol) in concentrated ammonium hydroxide (50 mL, 1284mmol) was heated at 100° C. in a high-pressure (350 mL) vesselovernight. The reaction mixture was cooled and concentrated in vacuum togive crude7-(3,5-difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(740 mg, 2.80 mmol, 106% yield). LC-MS (M+H)⁺=265.0.

Preparation S2,4-Dichloro-7-(3,5-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of7-(3,5-difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(740 mg, 2.80 mmol) in phosphoryl trichloride (7.691 mL, 84 mmol) washeated in microwave at 110° C. for 1 h. The reaction mixture was pouredinto ice. Once ice melted, the product was extracted withdichloromethane. The combined organic extracts were dried over anhydrousmagnesium sulfate and filtered. The solvent was removed in vacuum andthe residue was purified by column chromatography on silica gel to give2,4-dichloro-7-(3,5-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(200 mg, 0.664 mmol, 23.72% yield). LC-MS (M+H)⁺=301.0.

Preparation Sa2-Chloro-7-(3,5-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-(3,5-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(200 mg, 0.664 mmol) and methanamine (0.664 mL, 1.328 mmol) in MeOH (3mL) was stirred at rt for 1 h. The solvent was removed in vacuum and thecrude product was purified by column chromatography on silica gel togive2-chloro-7-(3,5-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(60 mg, 0.203 mmol, 30.5% yield). LC-MS (M+H)⁺=296.1.

Preparation T2,4-Dichloro-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Intermediate T(1)

(1S,2R)-2-(3,4,5-Trifluorophenyl)cyclopentanol

To a suspension of magnesium (2.88 g, 118 mmol) in THF (110 mL) wasslowly added 5-bromo-1,2,3-trifluorobenzene (25 g, 118 mmol). After theaddition, the reaction mixture was heated at reflux for 2 h. To thisreaction mixture, copper (I) iodide (1.506 g, 7.91 mmol) and6-oxabicyclo[3.1.0]hexane (9.93 g, 118 mmol) dissolved in THF (20 mL)were added dropwise. The reaction mixture warmed upon the addition ofthe epoxide. The reaction was stirred at rt for 2 h at rt. The reactionmixture was quenched by the addition of a solution of ammonium chloride.Ether was added and the organic layer was collected, dried (Na₂SO₄) andconcentrated. The crude product was purified by column chromatography onsilica gel to give (1S,2R)-2-(3,4,5-trifluorophenyl)cyclopentanol (20.2g, 93 mmol, 79% yield).

¹H NMR (500 MHz, CDCl₃) δ ppm 6.79-7.02 (2H, m), 4.10-4.21 (1H, m),2.75-2.91 (1H, m), 2.08-2.24 (2H, m), 1.75-1.93 (2H, m), 1.50-1.75 (2H,m).

Intermediate T(2)

2-(3,4,5-Trifluorophenyl)cyclopentanone

To a solution of (1S,2R)-2-(3,4,5-trifluorophenyl)cyclopentanol (1 g,4.63 mmol) in CH₂Cl₂ (20 mL) was added Dess-Martin periodinane (2.354 g,5.55 mmol). The reaction mixture was stirred at rt for 1 h. The reactionwas diluted with dichloromethane and quenched with the addition of 1 NNaOH. The organic layer was collected, dried (Na₂SO₄) and concentrated.The crude product was purified by column chromatography on silica gel toafford 2-(3,4,5-trifluorophenyl)cyclopentanone (310 mg, 1.447 mmol,31.3% yield). LC-MS (M+H)⁺=215.1.

Intermediate T(3)

7-(3,4,5-Trifluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione

A mixture of 2-(3,4,5-trifluorophenyl)cyclopentanone (2 g, 9.34 mmol)and carbonisocyanatidic chloride (1.773 g, 16.81 mmol) was heated at 58°C. for 1 h and at 130° C. for 2 h. Upon cooling to room temperature, thereaction mixture was dissolved in ethyl acetate and washed withsaturated aqueous solution of sodium bicarbonate. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic extracts were dried over anhydrous magnesium sulfateand filtered. The solvent was removed in vacuum and the residue waspurified by column chromatography on silica gel to give7-(3,4,5-trifluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(1.227 g, 4.33 mmol, 46.4% yield). LC-MS (M+H)⁺=284.0.

Intermediate T(4)

7-(3,4,5-Trifluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

A solution of7-(3,4,5-trifluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(1.23 g, 4.34 mmol) in concentrated ammonium hydroxide (75 mL, 1926mmol) was heated at 100° C. in a high-pressure (350 mL) vesselovernight. The reaction mixture was cooled and concentrated in vacuum togive crude7-(3,4,5-trifluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(1.3 g, 4.61 mmol, 106% yield). LC-MS (M+H)⁺=283.0.

Preparation T2,4-Dichloro-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of7-(3,4,5-trifluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(1.3 g, 4.61 mmol) in phosphoryl trichloride (5 mL, 54.6 mmol) washeated in microwave at 110° C. for 1 h. The reaction was repeated withan additional 800 mg of the starting material. The reaction mixtures waspoured into ice and combined. Once ice melted, the product was extractedwith dichloromethane. The combined organic extracts were dried overanhydrous magnesium sulfate and filtered. The solvent was removed invacuum and the residue was purified by column chromatography on silicagel to give2,4-dichloro-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(498 mg, 1.561 mmol, 33.9% yield). LC-MS (M+H)⁺=318.9.

Preparation Ta2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

A solution of2,4-dichloro-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(498 mg, 1.561 mmol) and methanamine (1.561 mL, 3.12 mmol) in MeOH (10mL) was stirred at rt for 1 h. Incomplete reaction was observed.Additional portions of methanamine (1.561 mL, 3.12 mmol) were added tothe reaction mixture until the reaction was complete. The solvent wasremoved in vacuum and the residue was purified by column chromatographyon silica gel to give2-chloro-7-(3,5-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(60 mg, 0.203 mmol, 30.5% yield). LC-MS (M+H)⁺=314.0.

Preparation Tb

2-Chloro-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of2,4-dichloro-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(100 mg, 0.313 mmol), DIPEA (0.066 mL, 0.376 mmol) and3,3-difluoropyrrolidine, HCl salt (45.0 mg, 0.313 mmol) were stirred atrt for 1 h. The solvent was removed in vacuum and the residue waspurified by column chromatography on silica gel to give2-chloro-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(105 mg, 0.269 mmol, 86% yield). LC-MS (M+H)⁺=390.0.

Preparation Tc2-Chloro-4-(3,3-difluoroazetidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of2,4-dichloro-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(100 mg, 0.313 mmol), DIPEA (0.109 mL, 0.627 mmol) and3,3-difluoroazetidine, HCl salt (44.7 mg, 0.345 mmol) were stirred at rtfor 1 h. The solvent was removed in vacuum and the residue was purifiedby column chromatography on silica gel to give2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(105 mg, 0.279 mmol, 89% yield). LC-MS (M+H)⁺=376.0.

Preparation U2,4-Dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Intermediate U(1)

1-Cyclopentenyl-2,4-difluorobenzene

To a 0.497M solution of (2,4-difluorophenyl)magnesium bromide (32.4 g,149 mmol) in THF at 0° C. was carefully added cyclopentanone (13.23 mL,149 mmol). Upon the end of the addition, the reaction mixture was heatedat reflux for 2 h. Ice (10 g) and 6N aqueous hydrochloric acid wereadded. The reaction mixture was extracted with ether. The combinedorganic extracts were washed with a saturated aqueous solution of sodiumhydrogen sulfite, a saturated aqueous solution of sodium bicarbonate andwater. The organic layer was dried over anhydrous magnesium sulfate andfiltered. The solvent was removed in vacuum and the residue was purifiedby column chromatography on silica gel to give1-cyclopentenyl-2,4-difluorobenzene (7.064 g, 39.2 mmol, 26.3% yield) ascolorless oil. LC-MS (M+H)⁺=181.0. ¹H NMR (500 MHz, CDCl₃) δ ppm7.22-7.31 (1H, m), 6.75-6.85 (2H, m), 6.26-6.31 (1H, m), 2.68-2.74 (2H,m), 2.51-2.58 (2H, m), 1.93-2.02 (2H, m).

Intermediate U(2)

2-(2,4-Difluorophenyl)cyclopentanone

A mixture of 90% formic acid (26.4 mL, 689 mmol) and 30% hydrogenperoxide (6.0 mL, 39.2 mmol) was warmed at 40° C. for 10 min. Theresulting solution was carefully added to1-cyclopentenyl-2,4-difluorobenzene (7.064 g, 39.2 mmol) under stirring.The two-phase system was initially stirred at room temperature. After acertain period of time, a spontaneous exothermic reaction took place,and the temperature rose to about 50° C. The reaction mixture wasstirred at room temperature for 2 h. The reaction mixture was quenchedby careful addition of a saturated sodium bicarbonate solution. Etherwas added and the content of the separatory funnel was vigorouslyshaken. The organic layer was separated and the aqueous layer wasextracted with ether. The combined organic extracts were dried overanhydrous magnesium sulfate and filtered. The solvent was removed invacuum and the residue was purified by column chromatography on silicagel to give 2-(2,4-difluorophenyl)cyclopentanone (3.503 g, 17.85 mmol,45.5% yield) as colorless oil. LC-MS (M+H)⁺=195.2. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.08 (1H, td, J=8.4, 6.4 Hz), 6.76-6.86 (2H, m), 3.42 (1H,dd, J=12.2, 8.9 Hz), 2.42-2.53 (2H, m), 2.28-2.39 (1H, m), 2.13-2.23(1H, m), 1.86-2.10 (2H, m).

Intermediate U(3)

7-(2,4-Difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione

A mixture of 2-(2,4-difluorophenyl)cyclopentanone (1.014 g, 5.17 mmol)and 50% wt. carbonisocyanatidic chloride solution in toluene (1.963 g,9.30 mmol) was heated at 58° C. for 1 h and at 120° C. for 3 h. Thereaction mixture was dissolved in ethyl acetate and washed with anaqueous solution of sodium bicarbonate. The organic layer was separatedand the aqueous layer was extracted with ethyl acetate. The combinedorganic extracts were dried over anhydrous magnesium sulfate andfiltered. The solvent was removed in vacuum and the residue was purifiedby column chromatography on silica gel to give7-(2,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(499.3 mg, 1.883 mmol, 36.4% yield) as brown solid. LC-MS (M+H)⁺=266.2.¹H NMR (500 MHz, CDCl₃) δ ppm 8.19-8.64 (1H, m), 7.10 (1H, td, J=8.5,6.3 Hz), 6.78-6.92 (2H, m), 4.36-4.49 (1H, m), 2.79-2.92 (1H, m),2.59-2.78 (2H, m), 2.08 (1H, ddd, J=9.3, 6.9, 6.7 Hz).

Intermediate U(4)

7-(2,4-Difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

A mixture of 2-(2,4-difluorophenyl)cyclopentanone (1.014 g, 5.17 mmol)and 50% wt. carbonisocyanatidic chloride solution in toluene (1.963 g,9.30 mmol) was heated at 58° C. for 1 h and at 120° C. for 3 h. Thereaction mixture was dissolved in ethyl acetate and washed with anaqueous solution of sodium bicarbonate. The organic layer was separatedand the aqueous layer was extracted with ethyl acetate. The combinedorganic extracts were dried over anhydrous magnesium sulfate andfiltered. The solvent was removed in vacuum and the residue was purifiedby column chromatography on silica gel to give7-(2,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(499.3 mg, 1.883 mmol, 36.4% yield) as brown solid. LC-MS (M+H)⁺=265.1.

Preparation U2,4-Dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A solution of7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (248.5mg, 0.940 mmol) in phosphoryl trichloride (10 mL) was heated inmicrowave at 130° C. for 2 h. The reaction mixture was poured in abeaker with ice. Once ice melted, the product was extracted withdichloromethane. The combined organic extracts were dried over anhydrousmagnesium sulfate and filtered. The solvent was removed in vacuum andthe residue was purified by column chromatography on silica gel to give2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (267.9 mg,95%) as light brown solid. LC-MS (M+H)⁺=301.1.

Preparation Ua2-Chloro-7-(2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-(2,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(267.9 mg, 0.890 mmol) in methanol (5 mL) was added a 2M solution ofmethylamine in methanol (0.890 mL, 1.779 mmol). The reaction mixture wasstirred at room temperature overnight. The solvent was removed in vacuumand the residue was partitioned between ethyl acetate and water. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The combined organic extracts were dried over anhydrousmagnesium sulfate and filtered. The solvent was removed in vacuum andthe residue was purified by column chromatography on silica gel to give2-chloro-7-(2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(184.6 mg, 0.624 mmol, 70.2% yield) as brown solid. LC-MS (M+H)⁺=296.1.

Preparation V2,4-dichloro-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Intermediate V(1)

2-methyl-2-phenylcyclopentanone

To a slurry of 60% NaH (125 mg, 3.12 mmol) in DME (3571 μL) at 0° C. wasadded 2-phenylcyclopentanone (500 mg, 3.12 mmol). After stirring for 1h, Met (898 μL, 14.36 mmol) was added, and the solution heated to refluxfor 2 h. The reaction was poured onto ice and extracted 3 times intoEt₂₀. The organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. Applied to Silica gel and elutedwith an EtOAc/Hex gradient to afford 2-methyl-2-phenylcyclopentanone(401.7 mg, 2.305 mmol, 73.9% yield). LC-MS (M+H)⁺=175.1. ¹H NMR (500MHz, CDCl₃) δ ppm 7.29-7.37 (4H, m), 7.20-7.24 (1H, m), 2.54 (1H, dt,J=12.51, 6.26 Hz), 2.34 (2 H, t, J=7.63 Hz), 1.82-2.05 (3H, m), 1.38(3H, s).

Intermediate V(2)

7-methyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione

Combined 2-methyl-2-phenylcyclopentanone (Intermediate V(1) (705.5 mg,4.05 mmol) and carbonisocyanatidic chloride (1700 mg, 8.06 mmol),flushed with N2, and sealed in a sealed tube. Heated at 58° C. for 1 h,then 130° C. for 1.75 h. Let cool to rt. Carefully opened the tube(HCl), and dissolved the residue in EtOAc. Partitioned with NaHCO₃ (aq),and extracted 3 times into EtOAc. Washed combined organic layers withbrine, dried over MgSO₄, filtered, and concentrated in vacuo. Loaded theresidue onto Silica gel and eluted with an EtOAc/Hexane gradient toafford7-methyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(43% yield)LC-MS (M+H)⁺=244.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.12 (1H,br. s.), 7.32-7.38 (2H, m), 7.26-7.30 (3H, m), 2.69-2.75 (2H, m),2.43-2.52 (1H, m), 2.21-2.29 (1H, m), 1.68 (3H, s).

Intermediate V(3)

7-methyl-7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

To solid7-methyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione(420 mg, 1.727 mmol) was added concentrated Ammonium Hydroxide (4706 μL,121 mmol) in a sealed tube. The tube was heated for 4 h at 80° C. Cooledto rt. Removed the solvent under a stream of N2. Loaded the residue ontoSilica gel and eluted with an EtOAc/Hexane gradient to afford7-methyl-7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(293 mg, 1.209 mmol, 70.0% yield). LC-MS (M+H)⁺=243.1.

Preparation V2,4-dichloro-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Dissolved7-methyl-7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione(48.2 mg, 0.199 mmol) in POCl₃ (742 μL, 7.96 mmol) and placed in amicrowave vial. Heated the reaction for 1 h at 120° C. in the microwave.Cooled to rt, and poured into ice. As soon as the ice melted, extracted3 times into EtOAc. Dried over MgSO₄, filtered, and concentrated invacuo. A quick EtOAc/Hex SG column provided2,4-dichloro-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine(43.1 mg, 0.154 mmol, 78% yield). LC-MS (M+H)⁺=279.1.

Preparation Va2-chloro-N-ethyl-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2,4-dichloro-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation V) (43.1 mg, 0.154 mmol) in THF (772 μL) at rt was added asolution of 2M Ethylamine (386 μL, 0.772 mmol) diluted with 390 uL MeOH(overall reaction is 0.1M in 1:1 THF/MeOH). Let stir at rt. Removed thesolvent and subjected the residue to a Silica gel column with anEtOAc/Hex gradient to afford2-chloro-N-ethyl-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(38.0 mg, 0.132 mmol, 86% yield).

Preparation W2,4-dichloro-7-allyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Intermediate W(1)

2-allyl-2-phenylcyclopentanone

The procedure of Intermediate V(1) was utilized with allyl bromide toobtain 2-allyl-2-phenylcyclopentanone.

Intermediate W(2)

7-allyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione

The method of Intermediate V(2) was utilized to obtain7-allyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.06 (1H, br. s.), 7.23-7.43 (5H, m),5.59-5.72 (1H, m, J=17.09, 9.99, 7.21, 7.21 Hz), 5.08-5.23 (2H, m),2.73-2.87 (2H, m), 2.63-2.71 (2H, m), 2.38-2.49 (2H, m)

Intermediate W(3)

7-allyl-7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

The method of Intermediate V(3) was utilized to obtain7-allyl-7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione.LC-MS (M+H)⁺=269.1.

Preparation W2,4-dichloro-7-allyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

The method of Preparation V was used to obtain2,4-dichloro-7-allyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine.LC-MS (M+H)⁺=305.0.

Preparation Wa2-chloro-N-ethyl-7-allyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

Utilizing the procedure for Preparation Va,2-chloro-N-ethyl-7-allyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminewas obtained. LC-MS (M+H)⁺=314.1.

Preparation X2,4-dichloro-8-(3,5-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

Intermediate X(1)

3-iodo-4,4-dimethoxytetrahydro-2H-pyran

The mixture of trimethoxymethane (82 mL, 745 mmol) anddihydro-2H-pyran-4(3H)-one (14.92 g, 149 mmol) was cooled to 4° C. Addeddiiodine (37.8 g, 149 mmol) in lots and keep the temperature between 4°C. and 5° C. The reaction mixture was stirred at 4° C. for 10 min.Cooling bath was removed, stirred at 28° C. for 10 min. The mixture wascooled to 10° C. and stirred for 10 min, and then stirred at RT for 1 h.

The reaction mixture was diluted with CH₂Cl₂ and cooled in ice water.Slowly quenched with saturated Na₂S₂O₃ solution. The mixed layers wereseparated. The aqueous layer was extracted with CH2Cl2. The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The crude product was purified by column chromatography on silica gel togive 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (33.05 g, 121 mmol, 82%yield). ¹H NMR (500 MHz, CDCl₃) δ ppm 4.24 (1H, t, J=2.29 Hz), 3.93-4.02(1H, m), 3.83-3.92 (2H, m), 3.55 (1H, d, J=2.44 Hz), 3.24 (3H, s), 3.20(3 H, s), 2.33 (1H, dd, J=4.88, 2.14 Hz), 1.79 (1H, dd, J=14.34, 2.44Hz)

Intermediate X(2) 3-(3,5-difluorophenyl)dihydro-2H-pyran-4(3H)-one

To a mixture of (1R,2R)-2-aminocyclohexanol hydrochloride (0.418 g, 2.76mmol), nickel(II) chloride hexahydrate (0.328 g, 1.378 mmol) and3,5-difluorophenylboronic acid (6.53 g, 41.3 mmol) was added NaHMDS inTHF (55.1 mL, 55.1 mmol) at 10° C. dropwise under N₂. After addition,the mixture was stirred at 10° C. for 20 min. 2-Propanol (113 mL)(previously bubbled by N2) was added at 0° C. and then the mixture wasstirred at RT for 10 min. 3-iodo-4,4-dimethoxytetrahydro-2H-pyran(Preparation X1) (7.5 g, 27.6 mmol). in THF was added dropwise and themixture was heated at 60° C. overnight. The reaction mixture was cooledin ice bath, added 1.0 HCl until acidic and stirred for 10 min.Concentrated in vacuum. Extracted with EtOAc and the organic layer waswashed with brine and concentrated. The residue was purified by columnchromatography on silica gel to give3-(3,5-difluorophenyl)dihydro-2H-pyran-4(3H)-one (1.6 g, 7.54 mmol,27.4% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm 6.78 (dd, J=8.24, 2.14 Hz,2H) 6.62-6.75 (m, 1H) 4.21 (dd, J=11.44, 5.65 Hz, 2H) 3.85-4.01 (m, 2H)3.76 (dd, J=8.55, 6.10 Hz, 1H) 2.60-2.75 (m, 1H) 2.48-2.60 (m, 1H)

Intermediate X(3)

8-(3,5-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione

The mixture of 3-(3,5-difluorophenyl) dihydro-2H-pyran-4(3H)-one(Preparation X2) (800 mg, 3.77 mmol) and carbonisocyanatidic chloride(557 mg, 5.28 mmol) was heated in a sealed bottle at 55° C. for 1 h andthen at 130° C. for 2 h. The mixture was cooled to RT. Partition betweenEtOAc and saturated NaHCO₃ solution. Extracted with EtOAc(×3 times). Thecombined organic layers was washed with brine, dried over Na₂SO₄ andconcentrated. The crude product was purified by column chromatography onsilica gel to give8-(3,5-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione(230 mg, 0.818 mmol, 21.69% yield). LC-MS (M+H)⁺=282.0. ¹H NMR (500 MHz,CDCl₃) δ ppm 8.94 (br, s., 1H) 6.85-7.01 (m, 2H) 6.81 (tt, J=8.81, 2.17Hz, 1H) 4.70 (d, J=15.56 Hz, 1H) 4.49 (dd, J=15.56, 2.14 Hz, 1H)4.03-4.12 (m, 2H) 3.68 (br. s., 1H)

Intermediate X(4)

8-(3,5-difluorophenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione

The mixture of8-(3,5-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione(Preparation X3)(230 mg, 0.818 mmol) and ammonium hydroxide (2229 mL,57.3 mmol) in a sealed bottle was heated at 80° C. for 4 h. Blowed by N2overnight to get8-(3,5-difluorophenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione(191 mg, 0.682 mmol, 83% yield) which was used as is. LC-MS(M+H)⁺=281.1.

Preparation X2,4-dichloro-8-(3,5-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

The mixture of8-(3,5-difluorophenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione(Intermediate X(4)) (191 mg, 0.682 mmol) and POCl₃ (1906 mL, 20.45 mmol)in a microwave vial was heated by microwave at 100° C. for 2.5 h. Themixture was poured on ice, as long as ice was melted, extracted withEtOAc (×3 times), washed with brine, dried over Na₂SO₄ and concentrated.The crude product was purified by column chromatography on silica gel togive2,4-dichloro-8-(3,5-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(117 mg, 0.369 mmol, 54.1% yield). LC-MS (M+H)⁺=317.1. ¹H NMR (400 MHz,CDCl₃) δ ppm 6.66-6.91 (m, 3H) 4.87-5.01 (m, 1H) 4.70-4.83 (m, 1H)4.13-4.27 (m, 2H) 4.10 (t, J=4.03 Hz, 1H)

Preparation Xa2-chloro-8-(3,5-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

The mixture of ethanamine (406 μL, 0.812 mmol),2,4-dichloro-8-(3,5-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation X)(117 mg, 0.369 mmol) and DIEA (161 μL, 0.922 mmol) in THF(1845 μL) was stirred at RT for 2 h. The mixture was concentrated andpurified by column chromatography on silica gel to give2-chloro-8-(3,5-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(104 mg, 0.319 mmol, 87% yield). LC-MS (M+H)⁺=326.1.

Preparation Y2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

Intermediate Y(2)

3-(3,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one

3,4-difluorophenylboronic acid was reacted as described in IntermediateX(2) with 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate X(1)) togive 3-(3,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one (IntermediateY(2)).

¹H NMR (500 MHz, CDCl₃) δ ppm 7.03-7.22 (m, 2H) 6.95 (ddd, J=6.33, 4.20,1.98 Hz, 1H) 4.17-4.32 (m, 2H) 3.96 (ddd, J=11.52, 9.84, 3.97 Hz, 1H)3.91 (dd, J=11.44, 9.00 Hz, 1H) 3.77 (dd, J=8.85, 5.80 Hz, 1H) 2.63-2.76(m, 1H) 2.49-2.62 (m, 1H).

Intermediate Y(3)

8-(3,4-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione

3-(3,4-difluorophenyl)dihydro-2H-pyran-4(3H)-one (Intermediate Y(2)) wasreacted as described in Intermediate X(3) with carbonisocyanatidicchloride to give8-(3,4-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione(Intermediate Y(3)). LC-MS (M+H)⁺=282.1. ¹H NMR (500 MHz, CDCl₃) δ ppm7.08-7.20 (m, 3H) 4.67 (d, J=15.26 Hz, 1H) 4.46 (dd, J=15.56, 2.14 Hz,1H) 3.98-4.10 (m, 2H) 3.67 (br. s., 1H).

Intermediate Y(4)

8-(3,4-difluorophenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione

8-(3,4-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione(Intermediate Y(3)) was reacted as described in Intermediate X(4) withammonium hydroxide to give8-(3,4-difluorophenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione(Intermediate Y(4)). LC-MS (M−H)⁺=279.1.

Preparation Y2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Intermediate Y(4)) was reacted as described in Preparation X with POCl₃to give2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Y). LC-MS (M+H)⁺=317.1.

Preparation Ya2-chloro-8-(3,4-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Y) was reacted as described in Preparation Xa withethanamine to give2-chloro-8-(3,4-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Ya). LC-MS (M+H)⁺=326.1.

Preparation Yb2-chloro-4-(3,3-difluoroazetidin-1-yl)-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Y) was reacted as described in Preparation Xa with3,3-difluoroazetidine, HCl to give2-chloro-4-(3,3-difluoroazetidin-1-yl)-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Yb). LC-MS (M+H)⁺=374.1.

Preparation Yc2-chloro-8-(3,4-difluorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Y) was reacted as described in Preparation Xa withmethanamine to give2-chloro-8-(3,4-difluorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Yc). LC-MS (M+H)⁺=312.3.

Preparation Z2,4-dichloro-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

Intermediate Z(2)

3-(4-(trifluoromethyl)phenyl)dihydro-2H-pyran-4(3H)-one

4-(trifluoromethyl)phenylboronic acid was reacted as described inIntermediate X(2) with 3-iodo-4,4-dimethoxytetrahydro-2H-pyran(Intermediate X(1)) to give3-(4-(trifluoromethyl)phenyl)dihydro-2H-pyran-4(3H)-one (IntermediateZ(2)).

¹H NMR (500 MHz, CDCl₃) δ ppm 7.61 (m, J=8.24 Hz, 2H) 7.37 (m, J=7.93Hz, 2H) 4.26 (dd, J=11.44, 5.95 Hz, 2H) 3.93-4.05 (m, 2H) 3.82-3.93 (m,1H) 2.64-2.81 (m, 1H) 2.49-2.64 (m, 1H)

Intermediate Z(3)

8-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione

3-(4-(trifluoromethyl)phenyl)dihydro-2H-pyran-4(3H)-one (IntermediateZ(2)) was reacted as described in Intermediate X(3) withcarbonisocyanatidic chloride to give8-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione(Intermediate Z(3)).

¹H NMR (500 MHz, CDCl₃) δ ppm 9.47 (br. s., 1H) 7.58-7.75 (m, 2H)7.42-7.55 (m, 2H) 4.68 (d, J=15.56 Hz, 1H) 4.42-4.57 (m, 1H) 4.03-4.22(m, 2H) 3.79 (br. s., 1H)

Intermediate Z(4)

8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione

8-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione(Intermediate Z(3)) was reacted as described in Intermediate X(4) withammonium hydroxide to give8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione(Intermediate Z(4)). LC-MS (M−H)⁺=313.1.

Preparation Z2,4-dichloro-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione(Intermediate Z(4)) was reacted as described in Preparation X with POCl₃to give2,4-dichloro-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Z). LC-MS (M+H)⁺=349.1.

Preparation Za2-chloro-N-ethyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

2,4-dichloro-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Z) was reacted as described in Preparation Xa withethanamine to give2-chloro-N-ethyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Za). LC-MS (M+H)⁺=358.1.

Preparation Zb2-chloro-N-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

2,4-dichloro-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Z) was reacted as described in Preparation Xa withmethanamine to give2-chloro-N-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Zb). LC-MS (M+H)⁺=344.1.

Preparation Zc2-chloro-N—((R)-1-cyclopropylethyl)-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

2,4-dichloro-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Z) was reacted as described in Preparation Xa with(R)-1-cyclopropylethanamine, HCl to give2-chloro-N—((R)-1-cyclopropylethyl)-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Zc). LC-MS (M+H)⁺=398.2.

Preparation AAa4-(2-chloro-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile

Intermediate AA(2)

4-(4-oxotetrahydro-2H-pyran-3-yl)benzonitrile

4-cyanophenylboronic acid was reacted as described in Intermediate X(2)with 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate X(1)) to give4-(4-oxotetrahydro-2H-pyran-3-yl)benzonitrile (Intermediate AA(2)).LC-MS (M+H)⁺=202.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.66 (d, J=8.24 Hz,2H) 7.38 (d, J=8.55 Hz, 2H) 4.23-4.31 (m, 2H) 3.94-4.02 (m, 2H)3.85-3.92 (m, 1H) 2.55-2.65 (m, 1H) 2.52 (t, J=5.80 Hz, 1H).

Intermediate AA(3)

4-(2,4-dioxo-2,3,4,5,7,8-hexahydropyrano[3,4-e][1,3]oxazin-8-yl)benzonitrile

4-(4-oxotetrahydro-2H-pyran-3-yl)benzonitrile (Intermediate AA(2)) wasreacted as described in Intermediate X(3) with carbonisocyanatidicchloride to give4-(2,4-dioxo-2,3,4,5,7,8-hexahydropyrano[3,4-e][1,3]oxazin-8-yl)benzonitrile(Intermediate AA(3)). LC-MS (M+H)⁺=271.1. ¹H NMR (400 MHz, CDCl₃) δ ppm7.57-7.78 (m, 2H) 7.41-7.51 (m, 2H) 4.61-4.75 (m, 1H) 4.50 (dd, J=15.49,2.14 Hz, 1H) 4.04-4.20 (m, 2H) 3.78 (br. s., 1H).

Intermediate AA(4)

4-(2,4-dioxo-2,3,4,5,7,8-hexahydro-1H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile

4-(2,4-dioxo-2,3,4,5,7,8-hexahydropyrano[3,4-e][1,3]oxazin-8-yl)benzonitrile(Intermediate AA(3)) was reacted as described in Intermediate X(4) withammonium hydroxide to give4-(2,4-dioxo-2,3,4,5,7,8-hexahydro-1H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile(Intermediate AA(4)). LC-MS (M−H)⁺=270.2.

Preparation AA4-(2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile

4-(2,4-dioxo-2,3,4,5,7,8-hexahydro-1H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile(Intermediate AA(4)) was reacted as described in Preparation X withPOCl₃ to give4-(2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile(Preparation AA). LC-MS (M+H)⁺=306.1.

Preparation AAa4-(2-chloro-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile

4-(2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile(Preparation AA) was reacted as described in Preparation Xa withethanamine to give4-(2-chloro-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile(Preparation AAa). LC-MS (M+H)⁺=315.1.

Preparation Ab2,4-dichloro-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

Intermediate AB(2)

3-(4-(trifluoromethoxy)phenyl)dihydro-2H-pyran-4(3H)-one

The procedure of Intermediate X(2) was utilized with4-(trifluoromethoxy)phenylboronic acid to obtain3-(4-(trifluoromethoxy)phenyl)dihydro-2H-pyran-4(3H)-one. ¹H NMR (400MHz, CDCl₃) δ ppm 7.29 (2H, d, J=7.05 Hz), 7.19-7.25 (2H, m), 4.23-4.32(2H, m), 3.91-4.04 (2H, m), 3.84 (1H, dd, J=8.81, 6.30 Hz), 2.66-2.77(1H, m), 2.56-2.63 (1H, m)

Intermediate AB(3)

8-(4-(trifluoromethoxy)phenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione

The procedure of Intermediate X(3) was utilized to obtain8-(4-(trifluoromethoxy)phenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione.¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.98 (1H, s), 7.52 (2H, d, J=8.55 Hz),7.37 (2H, d, J=7.93 Hz), 4.45-4.51 (1H, m), 4.36 (1H, dd, J=14.95, 2.14Hz), 4.00-4.08 (2H, m), 3.82 (1H, dd, J=10.68, 3.36 Hz).

Intermediate AB(4)

8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione

The procedure of Intermediate X(4) was utilized to obtain8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione.LC-MS (M+H)⁺=329.0.

Preparation Ab2,4-dichloro-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

The procedure of Preparation X was utilized to obtain2,4-dichloro-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine.LC-MS (M+H)⁺=365.0.

Preparation Aba2-chloro-N-methyl-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

To a solution of2,4-dichloro-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation AB) (80.7 mg, 0.221 mmol) in MeOH (2210 μL) was addedmethylamine (1000 μL, 2.0 mmol) (2M in THF). The reaction was allowed tostir overnight. Removed the solvent and applied to silica gel, elutingwith an EtOAc/Hex gradient to afford2-chloro-N-methyl-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(69.8 mg, 0.194 mmol, 88% yield). LC-MS (M+H)⁺=360.0.

Preparation Abb2-chloro-4-((R)-3-fluoropyrrolidin-1-yl)-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

To a solution of2,4-dichloro-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation AB) (56.4 mg, 0.154 mmol) in MeOH (1545 μL) was added DIPEA(67.4 μL, 0.386 mmol), then solid (R)-3-fluoropyrrolidine, HCl (21.34mg, 0.170 mmol). The reaction was allowed to stir at rt. Removed thesolvent and applied to silica gel. Eluted with a EtOAc/Hex gradient toafford the diasteriomeric mixture2-chloro-4-((R)-3-fluoropyrrolidin-1-yl)-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(57.6 mg, 0.138 mmol, 89% yield). LC-MS (M+H)⁺=418.1.

Preparation Ac 2,4-Dichloro-8-phenyl-5,6,7,8-tetrahydroquinazoline

Intermediate AC(1)

8-Phenyl-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(311)-dione

A solution of 2-phenylcyclohexanone (1.500 g, 8.61 mmol) andcarbonisocyanatidic chloride (0.966 mL, 12 mmol) was stirred at 58° C.in a high-pressure vessel (75 mL) for 1 h. The temperature was raised to130° C. and the reaction mixture was stirred for 2 h. After cooling toroom temperature, the reaction mixture solidified. The solid residue wasdissolved in ethyl acetate and washed with saturated aqueous solution ofsodium bicarbonate. The organic layer was separated and the aqueouslayer was extracted twice with ethyl acetate. The combined organicextracts were dried over anhydrous sodium sulfate and filtered. Thesolvent was removed in vacuum and the oily residue was purified bycolumn chromatography on silica gel to provide8-phenyl-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0mg, 1.689 mmol, 19.62% yield) as white solid and4a-phenyl-4a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione(746.4 mg, 3.04 mmol, 35.3% yield) as white solid.

8-phenyl-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(31-1)-dione.LC-MS (M+H)⁺=244.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.61 (1H, br s),7.22-7.38 (3H, m), 7.09-7.19 (2H, m), 3.81 (1H, t, J=4.9 Hz), 2.39-2.63(2H, m), 2.15 (1H, dddd, J=13.2, 9.8, 6.3, 3.1 Hz), 1.84-1.96 (1H, m),1.52-1.84 (2H, m).

4a-phenyl-4a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione.LC-MS (M+H)⁺=244.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.66 (1H, br s),7.40-7.46 (2H, m), 7.29-7.39 (3H, m), 5.99-6.06 (1H, m), 2.37 (1H, ddd,J=14.0, 3.4, 3.1 Hz), 2.10-2.29 (3H, m), 1.54-1.64 (1H, m), 1.21-1.36(1H, m).

Intermediate AC(2)

8-Phenyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione

A solution of8-phenyl-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0mg, 1.706 mmol) in concentrated ammonium hydroxide (35 mL, 899 mmol) wasstirred at 100° C. in a high-pressure vessel (75 mL) for 6 h. Theformation of white precipitate was observed during the heating. TheLC/MS analysis of the filtrate shows the presence of the product withthe desired mass (M+H)=243.20. The solvent was removed in vacuum toprovide 8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (435 mg,1.706 mmol, 100% yield) as off-white solid. LC-MS (M+H)⁺=243.2. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 10.2 (2H, br. s.), 7.34 (2H, t, J=7.5 Hz), 7.26(1H, t, J=7.3 Hz), 7.14 (2H, d, J=7.3 Hz), 3.80 (1H, br. s.), 2.32-2.43(1H, m), 2.15 (1H, ddd, J=16.9, 10.5, 6.1 Hz), 1.93-2.04 (1H, m),1.67-1.75 (1H, m), 1.56 (1H, ddd, J=7.8, 5.2, 2.6 Hz), 1.36 (1H, dt,J=13.1, 2.7 Hz).

Preparation Ac 2,4-Dichloro-8-phenyl-5,6,7,8-tetrahydroquinazoline

A mixture of 8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione(233.1 mg, 0.962 mmol), phosphorus oxychloride (2798 μL, 30.0 mmol) andN,N-dimethylaniline (933 μL, 7.36 mmol) was heated at 110° C. in acapped vial overnight. The reaction mixture was poured into a beakerwith ice and the inside of the reaction vessel was washed withdichloromethane. As soon as the ice completely melted, the content ofthe beaker was placed into a separatory funnel The organic layer wasseparated and the aqueous layer was extracted with dichloromethane. Thecombined organic extracts were dried over anhydrous sodium sulfate andfiltered. The solvent was removed in vacuum and the residue was purifiedby column chromatography on silica gel to provide2,4-dichloro-8-phenyl-5,6,7,8-tetrahydroquinazoline (320.3 mg, 83%) asyellow oil. LC-MS (M+H)⁺=279.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.28 (2H,t, J=7.5 Hz), 7.19-7.24 (1H, m), 6.95 (2H, d, J=7.3 Hz), 4.23 (1H, t,J=5.6 Hz), 2.82-2.92 (1H, m), 2.72-2.82 (1H, m), 2.10-2.22 (1H, m),1.97-2.06 (1H, m), 1.76-1.93 (2H, m).

Preparation ACa2-Chloro-N-ethyl-N-methyl-8-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine

To a solution of 2,4-dichloro-8-phenyl-5,6,7,8-tetrahydroquinazoline(53.9 mg, 0.193 mmol) in methanol (1 mL) was added N-methylethanamine(0.033 mL, 0.386 mmol). The reaction mixture was stirred at roomtemperature for 2 h. The solvent was removed in vacuum and the residuewas purified by column chromatography on silica gel to give2-chloro-N-ethyl-N-methyl-8-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine(42.9 mg, 0.141 mmol, 72.9% yield) as colorless oil. LC-MS (M+H)⁺=302.2.¹H NMR (500 MHz, CDCl₃) δ ppm 7.25 (2H, t, J=7.5 Hz), 7.13-7.20 (1H, m),7.01 (2H, d, J=7.3 Hz), 4.06-4.14 (1H, m), 3.42-3.53 (2H, m), 3.05 (3H,s), 2.56-2.74 (2H, m), 2.17-2.27 (1H, m), 1.76-1.89 (2H, m), 1.52-1.64(1H, m), 1.24 (3H, t, J=7.2 Hz).

Preparation ACb 2-Chloro-8-phenyl-5,6,7,8-tetrahydroquinazoline

A mixture of 2,4-dichloro-8-phenyl-5,6,7,8-tetrahydroquinazoline (51.9mg, 0.186 mmol), ammonium chloride (13.0 mg, 0.243 mmol) and zinc (130mg, 1.988 mmol) in acetone (0.75 mL) and water (0.75 mL) was heated at90° C. with stirring for 2 h. The reaction mixture was filtered througha short plug of diatomaceous earth (Celite®). The solvent was removed invacuum, and the residue was partitioned between dichloromethane andwater. The organic layer was separated and the aqueous layer wasextracted with dichloromethane. The combined organic extracts were driedover anhydrous magnesium sulfate and filtered. The solvent was removedin vacuum and the residue was purified by column chromatography onsilica gel to give 2-chloro-8-phenyl-5,6,7,8-tetrahydroquinazoline (24.1mg, 0.097 mmol, 52.4% yield) as white solid. LC-MS (M+H)⁺=245.1. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.39 (1H, s), 7.27 (2H, t, J=7.6 Hz), 7.16-7.23(1H, m), 6.95 (2H, d, J=7.3 Hz), 4.21 (1H, t, J=6.0 Hz), 2.72-2.91 (2H,m), 2.14-2.26 (1H, m), 1.95-2.06 (1H, m), 1.81-1.93 (1H, m), 1.71-1.81(1H, m).

Preparation AD2,4-dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline

Intermediate AD(1)

8-Phenyl-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione

2-(4-fluorophenyl)cyclohexanone and carbonisocyanatidic chloride (0.966mL, 12 mmol) was reacted as in Intermediate AC(1) to provide8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione(415.0 mg, 1.689 mmol, 19.62% yield) as white solid and4a-(4-fluorophenyl)-4a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione(746.4 mg, 3.04 mmol, 35.3% yield) as white solid.8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione.LC-MS (M+H)⁺=262.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.61 (1H, br s), 7.10(2H, dd, J=5.0, 8.5 Hz), 6.98 (2H, app t, J=8.5 Hz), 3.77 (1H, t, J=4.9Hz), 2.38-2.53 (2H, m), 2.16-2.07 (1H, m), 1.87-1.62 (3H, m).

Intermediate AD(2)

8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione

A solution of8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dionewas reacted in the manner of Intermediate AC(2) to provide8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. LC-MS(M+H)⁺=261.2.

Preparation AD2,4-dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline

A mixture of8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione wasreacted in the manner of Preparation AC to provide2,4-dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline, which wasnot characterized at this step.

Preparation ADa2-Chloro-N-ethyl-8-(4-fluorophenyl)-N-methyl-5,6,7,8-tetrahydroquinazolin-4-amine

A solution of2,4-dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (115 mg,0.387 mmol) and excess N-methylethanamine (0.332 mL, 3.87 mmol) in MeOH(2 mL) was stirred at room temperature for 30 min. The solvent wasremoved in vacuum to afford2-chloro-N-ethyl-8-(4-fluorophenyl)-N-methyl-5,6,7,8-tetrahydroquinazolin-4-amine(124 mg, 0.388 mmol, 100% yield). LC-MS (M+H)⁺=320.2.

Preparation ADb2-Chloro-8-(4-fluorophenyl)-N,N-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine

A solution of2,4-dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (115 mg,0.387 mmol) and excess dimethylamine (1.935 mL, 3.87 mmol) in MeOH (1mL) was stirred at room temperature for 1 h. The solvent was removed invacuum to afford2-chloro-8-(4-fluorophenyl)-N,N-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine(118 mg, 0.386 mmol, 100% yield). LC-MS (M+H)⁺=306.2.

Preparation ADc2-Chloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline

A mixture of2,4-dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (115 mg,0.387 mmol), Ammonium chloride (26.9 mg, 0.503 mmol) and zinc (266 mg,4.06 mmol) in acetone (1 mL) and water (1.000 mL) was heated at 90° C.with stirring for 2 h. The reaction mixture was filtered through a shortplug of celite. The solvent was removed in vacuum, and the residue waspartitioned between dichloromethane and water. The organic layer wasseparated and the aqueous layer was extracted with dichloromethane. Thecombined organic extracts were dried over anhydrous magnesium sulfateand filtered. The solvent was removed in vacuum and the residue waspurified by column chromatography on silica gel to give2-chloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (20 mg, 0.076mmol, 19.67% yield) as a white solid. LC-MS (M+H)⁺=263.2.

Preparation AE2,4-dichloro-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Intermediate AE(1)

Ethyl 2-cyano-2-phenylacetate

To a solution of sodium hydride (24.5 g, 1.02 mol) in THF was addedbenzyl cyanide (50.0 g, 0.426 mol) at −10° C. The reaction mixture wasstirred for 15 min at the same temperature. Diethyl carbonate (60.5 g,0.512 mol) was added to the reaction mixture and the reaction mixturewas allowed to come to room temperature and heated to 40° C. (Caution:Reaction will start suddenly and exothermic). The heating path wasremoved immediately once the reaction was started and the reactionmixture was cooled under ice/acetone. The solution was allowed to cometo room temperature and stirred for 1 h. The reaction mass was cooled to0° C. and quenched with aqueous saturated ammonium chloride andextracted with ethyl acetate (250 mL×3). The combined organic layer waswashed with water (200 mL), brine solution (200 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to give ethyl2-cyano-2-phenylacetate as crude compound as crude compound (71.0 g).The crude compound was taken to the next step without furtherpurification. LC-MS (M+H)⁺=190.1. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.45(5H, m), 5.65 (1H, s), 4.18 (2H, m), 1.18 (3H, t, J=7.2 Hz).

Intermediate AE(2)

ethyl 3-amino-2-phenylpropanoate

To a solution of Intermediate AE(1) (25.0 g, 0.132 mol) in methanol wasadded palladium on carbon (10%, w/w) followed by trifluoroacetic acid(2.0 vol., 50 mL) at room temperature. The reaction mixture washydrogenated under 5 kg of hydrogen pressure for 3 h. The reactionmixture was filtered through celite bed and washed with methanol. Thefiltrate was evaporated under reduced pressure and the residue wasneutralized with aqueous saturated bicarbonate solution. The aqueoussolution was extracted with ethyl acetate (200 mL×4). The combinedorganic layer was washed with brine solution (200 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to get crudecompound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 10% methanol in dichloromethane asmobile phase to give ethyl 3-amino-2-phenylpropanoate (17.0 g, 67%) asoily liquid. LC-MS (M+H)⁺=194.0. ¹H NMR (400 MHz, DMSO-d6): δ ppm7.42-7.2 (7H, m), 4.11 (2H, m), 4.09 (1H, m), 3.44 (1H, m), 3.09 (1H,m), 1.15 (3H, t, J=5.6 Hz).

Intermediate AE(3)

ethyl 3-(3-ethoxy-3-oxopropylamino)-2-phenylpropanoate

To a solution of Intermediate AE(2) (10.0 g, 51.7 mmol) in ethanol wasadded ethyl acrylate (4.1 g, 40.9 mmol) at room temperature. Thereaction mixture was stirred at the same temperature for 18 h. Thesolvent was evaporated under reduced pressure and the crude compound waspurified by column chromatography (Silica gel, 60-120 mesh) using 50%ethyl acetate in pet-ether as mobile phase to give ethyl3-(3-ethoxy-3-oxopropylamino)-2-phenylpropanoate (12.1 g, 80%) asyellowish oily liquid. LC-MS (M+H)⁺=294.1. ¹H NMR (400 MHz, CDCl₃): δppm 7.29 (5H, m), 4.11 (4H, m), 3.76 (1H, m), 3.26 (1H, m), 2.90 (3H,m), 2.44 (2H, m), 1.20 (6H, m).

Intermediate AE(4)

ethyl3-((3-ethoxy-3-oxopropyl)(4-methoxybenzyl)amino)-2-phenylpropanoate

To a solution Intermediate AE(3) (15.0 g, 51.1 mmol) in acetone wasadded K2CO3 (8.4 g, 61.4 mmol) followed by p-methoxybenzyl bromide (15.4g, 76.7 mmol) at room temperature. The reaction mixture was heated atreflux for 3 h. The solvent was removed under reduced pressure and theresidue was diluted with water. The aqueous layer was extracted withethyl acetate (100×3). The combined organic layer was washed with brinesolution (100 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (Silica gel, 60-120 mesh) using 30% ethylacetate in pet-ether as mobile phase to give ethyl3-((3-ethoxy-3-oxopropyl)(4-methoxybenzyl)amino)-2-phenylpropanoate(12.1 g, 60%) as oily liquid. LC-MS (M+H)⁺=414.2. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.27 (5H, m), 7.13, (2H, m), 6.82 (2H, m), 4.11 (4H, m),4.08 (3H, s), 4.06 (1H, m), 3.81 (1H, d, J=4.0 Hz), 3.79 (1H, d, J=4.0Hz), 3.25 (1H, m), 2.73 (3H, m), 2.43 (2H, m), 1.24 (6H, m).

Intermediate AE(5)

ethyl 1-(4-methoxybenzyl)-4-oxo-5-phenylpiperidine-3-carboxylate

To a cooled solution of Intermediate AE(4) (12.0 g, 29.0 mmol) in THFwas added t-BuOK (6.5 g, 58.0 mmol). The reaction mixture was stirred atroom temperature for 2 h. The reaction mass was quenched with water thenevaporated the solvent under reduced pressure. The residue was dilutedwith water and extracted with ethyl acetate (100 mL×2). The combinedorganic layer was washed with brine solution (100 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to get crudecompound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 25% ethyl acetate in pet-ether as mobilephase to give ethyl1-(4-methoxybenzyl)-4-oxo-5-phenylpiperidine-3-carboxylate (7.1 g, 67%)as oily liquid. LC-MS (M+H)⁺=368.2. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.26(4H, m), 7.15 (2H, m), 6.88 (2H, m), 4.15 (2H, m), 4.09 (3H, s), 3.82(2H, m), 3.66 (2H, m), 2.80 (3H, m), 2.40 (1H, m), 1.24 (3H, m).

Intermediate AE(6)

6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione

To a cooled solution of Intermediate AE(5) (7.0 g, 19.0 mmol) in ethanolwas added t-BuOK (5.3 g, 47.6 mmol) followed by urea (2.8 g, 47.6 mmol).The reaction mixture was heated at reflux for 24 h. The reaction masswas quenched with water and evaporated the solvent under reducedpressure. The residue was diluted with water and extracted with ethylacetate (100 mL×3). The combined organic layer was washed with brinesolution (100 mL), dried over Na₂SO₄ and evaporated under reducedpressure to get crude compound. The crude compound was purified bycolumn chromatography (Silica gel, 60-120 mesh) using 10% pet-ether inethyl acetate as mobile phase to give6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione(4.0 g, 57%) as pale yellow solid. LC-MS (M+H)⁺=364.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 11.05 (1H, s), 10.60 (1H, s), 7.30 (5H, m), 6.99 (2H,m), 6.77 (2H, m), 3.72 (2H, m), 3.57 (3H, s), 3.44 (1H, m), 3.34 (1H,m), 2.90 (1H, m), 2.51 (2H, m).

Preparation AE2,4-dichloro-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

A solution of Intermediate AE(6) (2.0 g, 5.5 mmol) and catalytic amountof DMF in POCl₃ (20 vol.) was heated at reflux for 10 h. The excess ofPOCl₃ was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 min. The aqueous solution wasextracted with ethyl acetate (75 mL×3). The combined organic layer waswashed with aqueous saturated NaHCO₃ (50 mL×2), brine solution (100 mL),dried over Na₂SO₄ and evaporated under reduced pressure to give2,4-dichloro-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine(1.5 g, 69%) as brown solid. LC-MS (M+H)⁺=400.0. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.30 (3H, m), 7.26 (4H, m), 6.81 (2H, m), 4.20 (1H, m),3.79 (2H, m), 3.72 (3H, s), 3.68 (2H, m), 3.57 (1H, m), 3.02 (1H, m),2.98 (1H, m).

Preparation AEa2-chloro-6-(4-methoxybenzyl)-N-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

To a solution of Preparation AE (1.1 g, 2.7 mmol) in acetonitrile wasadded diisopropylethylamine (1.0 g, 8.3 mmol) followed by addition ofmethylamine hydrochloride (0.28 g, 4.1 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified bycolumn chromatography (60-120 mesh) using 30% ethyl acetate in pet-etheras mobile phase to give2-chloro-6-(4-methoxybenzyl)-N-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine(0.8 g, 74%) as off-white solid. LC-MS (M+H)⁺=395.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 7.29 (4H, m), 7.16 (4H, m), 6.80 (2H, m), 3.93 (1H, m),3.73 (3H, s), 3.66 (2H, m), 3.57 (1H, m), 3.46 (1H, m), 3.23 (1H, m),2.67 (3H, d, J=4.0 Hz), 2.51 (1H, m).

Preparation AEb2-chloro-N-ethyl-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

To a solution of Preparation AE (1.6 g, 4.0 mmol) in acetonitrile wasadded diisopropylethylamine (1.5 g, 12.0 mmol) followed by addition ofethylamine hydrochloride (0.52 g, 6.0 mmol) at room temperature. Thereaction mixture was stirred at the same temperature for 18 h. Thesolvent was removed under reduced pressure and the residue was purifiedby column chromatography (60-120 mesh) using 30% ethyl acetate inpet-ether as mobile phase to give2-chloro-N-ethyl-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine(0.9 g, 56%) as off-white solid. LC-MS (M−H)⁺=407.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 7.31-7.12 (7H, m), 6.83-6.79 (2H, m), 4.47 (1H, bs),4.06 (1H, m), 3.83 (3H, s), 3.66 (2H, m), 3.58 (2H, m), 3.44 (1H, m),3.20 (1H, m), 3.08 (1H, m), 2.88 (1H, m), 1.25 (3H, d, J=7.2 Hz).

Preparation AEc2-chloro-N,N-dimethyl-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

Using the procedure of Preparation AEb, utilized dimethylamine toproduce2-chloro-N,N-dimethyl-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

Preparation AEdN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.229 g, 1.02 mmol), Preparation AEa (0.45g, 1.14 mmol), Na₂CO₃ (0.24 g, 2.28 mmol) and xantphos (0.659 g, 1.14mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.59 g, 0.57 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through celite bed and washed with ethyl acetate. The filtratewas evaporated under reduced pressure and the residue was diluted withwater. The aqueous solution was extracted with ethyl acetate (100 mL×2).The combined organic layer was washed with brine solution (100 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 5% ethyl acetate in dichloromethane asmobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.28 g, 43%) as off-white solid. LC-MS (M+H)⁺=582.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.06 (1H, s), 8.05 (1H, s), 7.71 (1H, s), 7.4 (1H, s),7.39-7.06 (11H, m), 6.79 (2H, m), 6.73 (1H, m), 3.93 (1H, m), 3.71 (3H,s), 3.62 (2H, m), 3.55 (3H, s), 3.46 (1H, m), 3.26 (1H, m), 2.92 (3H, d,J=4.4 Hz).

Preparation AEe

N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.442 g, 1.98 mmol), Preparation AEb (0.9g, 2.2 mmol), Na₂CO₃ (0.467 g, 4.4 mmol) and xantphos (1.27 g, 2.2 mmol)in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (1.1 g, 1.1 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through celite bed and washed with ethyl acetate. The filtratewas evaporated under reduced pressure and the residue was diluted withwater. The aqueous solution was extracted with ethyl acetate (100 mL×3).The combined organic layer was washed with brine solution (100 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 5% ethyl acetate in dichloromethane asmobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.71 g, 54%) as off-white solid. LC-MS (M+H)⁺=596.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.03 (1H, s), 7.98 (1H, s), 7.71 (1H, s), 7.40 (1H, s),7.27-7.10 (9H, m), 6.81-6.78 (2H, m), 6.72 (1H, m), 3.91 (1H, m), 3.71(3H, s), 3.65 (2H, m), 3.56 (3H, s), 3.51-3.49 (3H, m), 3.28 (1H, m),2.87 (1H, m), 2.65 (1H, m), 1.18 (3H, t, J=7.2 Hz).

Preparation AEfN2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(4-methoxybenzyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation B (0.175 g, 0.913 mmol), Preparation AEa (0.40g, 1.01 mmol), Na₂CO₃ (0.20 g, 2.02 mmol) and xantphos (0.585 g, 1.01mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.525 g, 0.50 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through celite bed and washed with ethyl acetate. The filtratewas evaporated under reduced pressure and the residue was diluted withwater. The aqueous solution was extracted with ethyl acetate (100 mL×2).The combined organic layer was washed with brine solution (100 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 5% ethyl acetate in dichloromethane asmobile phase to giveN2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(4-methoxybenzyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.24 g, 42%) as off-white solid. LC-MS (M+H)⁺=551.1.

Preparation AEgN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation B (0.423 g, 2.20 mmol), Preparation AEb (1.0g, 2.44 mmol), Na₂CO₃ (0.520 g, 4.89 mmol) and xantphos (1.41 g, 2.44mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (1.26 g, 1.22 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (100 mL×3). The combined organic layer was washedwith brine solution (100 mL), dried over anhydrous Na₂SO₄ and evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by column chromatography (Silica gel, 60-120 mesh) using 5%ethyl acetate in dichloromethane as mobile phase to giveN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.70 g, 53%) as off-white solid. LC-MS (M+H)⁺=565.2.

Preparation AEhN2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(4-methoxybenzyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation C (0.175 g, 0.913 mmol), Preparation AEa (0.40g, 1.01 mmol), Na₂CO₃ (0.20 g, 2.02 mmol) and xantphos (0.586 g, 1.01mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.525 g, 0.50 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (100 mL×2). The combined organic layer was washedwith brine solution (100 mL), dried over anhydrous Na₂SO₄ and evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by column chromatography (Silica gel, 60-120 mesh) using 5%ethyl acetate in dichloromethane as mobile phase to giveN2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(4-methoxybenzyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.27 g, 51%) as off-white solid. LC-MS (M+H)⁺=565.2.

Preparation AEiN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation C (0.423 g, 2.20 mmol), Preparation AEb (1.0g, 2.44 mmol), Na₂CO₃ (0.520 g, 4.89 mmol) and xantphos (1.41 g, 2.44mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (1.26 g, 1.22 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (100 mL×3). The combined organic layer was washedwith brine solution (100 mL), dried over anhydrous Na₂SO₄ and evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by column chromatography (Silica gel, 60-120 mesh) using 5%ethyl acetate in dichloromethane as mobile phase to giveN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.72 g, 54%) as off-white solid. LC-MS (M+H)⁺=565.4.

Preparation AEjN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEd (0.28 g, 0.48 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (25 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (50mL×2). The combined organic layer was washed with brine solution (50mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamineas crude compound (0.195 g). The crude compound was taken to the nextstep without further purification. LC-MS (M+H)⁺=462.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.03 (1H, s), 8.06 (1H, s), 7.71 (1H, s), 7.39 (1H, s),7.27-7.24 (2H, m), 7.18-7.05 (5H, m), 6.68 (1H, m), 5.76 (1H, s), 3.81(1H, m), 3.69-3.63 (2H, m), 3.57 (3H, s), 3.22 (1H, m), 2.95 (3H, d,J=4.0 Hz), 2.84 (1H, m).

Preparation AEkN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEe (0.25 g, 0.42 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (50 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (50mL×3). The combined organic layer was washed with brine solution (50mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamineas crude compound (0.19 g). The crude compound was taken to the nextstep without further purification. LC-MS (M+H)⁺=476.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.00 (1H, s), 7.99 (1H, s), 7.71 (1H, s), 7.40 (1H, s),7.28-7.24 (2H, m), 7.19-7.09 (6H, m), 5.76 (1H, m), 3.70 (1H, m), 3.58(2H, m), 3.51 (3H, s), 3.48 (2H, m), 3.25 (1H, m), 2.80 (1H, m), 1.20(3H, t, J=7.2 Hz).

Preparation AElN2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEf (0.24 g, 0.436 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (25 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (50mL×2). The combined organic layer was washed with brine solution (50mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamineas crude compound (0.190 g). The crude compound was taken to the nextstep without further purification. LC-MS (M+H)⁺=431.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.13 (1H, s), 8.66 (1H, s), 8.00 (1H, m), 7.43-7.36 (2H,m), 7.29-7.26 (3H, m), 7.25-7.17 (3H, m), 6.75 (1H, m), 5.78 (1H, m),3.83 (1H, m), 3.65 (2H, m), 3.33 (1H, m), 2.94 (3H, d, J=4.4 Hz), 2.33(3H, s).

Preparation AEmN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEg (0.490 g, 0.868 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (50 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (50mL×3). The combined organic layer was washed with brine solution (50mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN⁴-ethyl-N²-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamineas crude compound (0.220 g). The crude compound was taken to the nextstep without further purification. LC-MS (M+H)⁺=445.2.

Preparation AEnN2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEh (0.27 g, 0.490 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (25 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (50mL×2). The combined organic layer was washed with brine solution (50mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamineas crude compound (0.210 g). The crude compound was taken to the nextstep without further purification. LC-MS (M+H)⁺=551.2.

Preparation AEoN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEi (0.75 g, 1.32 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (50 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (50mL×3). The combined organic layer was washed with brine solution (50mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamineas crude compound (0.60 g). The crude compound was taken to the nextstep without further purification. LC-MS (M+H)⁺=445.2.

Preparation AEp1-(4-(ethylamino)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2,2,2-trifluoroethanone

To a solution of Preparation AEm (0.20 g, 0.449 mmol) in dichloromethanewas added triethylamine (0.068 g, 0.67 mmol) followed by trifluoroaceticanhydride (0.14 g, 0.67 mmol) and catalytic amount of DMAP at 0° C. Thereaction mixture was allowed to come to room temperature and stirred for18 h. The reaction mixture was diluted with dichloromethane, washed withaqueous saturated NaHCO₃ (25 mL), brine solution (20 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to give1-(4-(ethylamino)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2,2,2-trifluoroethanoneas crude compound (0.18 g, 74%). The crude compound was taken to thenext step without further purification. LC-MS (M+H)⁺=541.2.

Preparation AEq1-(4-(ethylamino)-2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2,2,2-trifluoroethanone

To a solution of Preparation AEo (0.21 g, 0.47 mmol) in dichloromethanewas added triethylamine (0.071 g, 0.70 mmol) followed by trifluoroaceticanhydride (0.15 g, 0.70 mmol) and catalytic amount of DMAP at 0° C. Thereaction mixture was allowed to come to room temperature and stirred for18 h. The reaction mixture was diluted with dichloromethane, washed withaqueous saturated NaHCO₃ (25 mL), brine solution (20 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to give1-(4-(ethylamino)-2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2,2,2-trifluoroethanoneas crude compound (0.185 g, 73%). The crude compound was taken to thenext step without further purification. LC-MS (M+H)⁺=541.2.

Preparation AF2,4-dichloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Intermediate AF(1)

ethyl3-((3-ethoxy-3-oxopropyl)(methyl)amino)-2-(4-fluorophenyl)propanoate

To a solution of Intermediate AE(3) (4.0 g, 13.65 mmol) in acetone wasadded K₂CO₃ (3.7 g, 27.3 mmol) followed by methyl iodide (2.3 g, 16.3mmol) at 0° C. The reaction mixture was stirred at room temperature for2 h. The solvent was removed under reduced pressure and the residue wasdiluted with water. The aqueous layer was extracted with ethyl acetate(25×3). The combined organic layer was washed with brine solution (50mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto get crude compound. The crude compound was purified by columnchromatography (Silica gel, 60-120 mesh) using 40% ethyl acetate inpet-ether as mobile phase to give ethyl3-((3-ethoxy-3-oxopropyl)(methyl)amino)-2-phenylpropanoate (0.9 g, 22%)as oily liquid. LC-MS (M+H)⁺=308.0. ¹H NMR (400 MHz, DMSO-d): δ ppm7.33-7.26 (5H, m), 4.07-4.01 (4H, m), 3.83 (1H, m), 3.07 (1H, m),2.69-2.52 (2H, m), 2.47-2.41 (3H, m), 2.21 (3H, s), 1.19-0.10 (6H, m).

Intermediate AF(2)

ethyl 1-methyl-4-oxo-5-phenylpiperidine-3-carboxylate

To a cooled solution of Intermediate AF(1) (0.9 g, 2.93 mmol) in THF wasadded t-BuOK (0.65 g, 5.86 mmol). The reaction mixture was stirred atroom temperature for 2 h. The reaction mass was quenched with water thenevaporated the solvent under reduced pressure. The residue was dilutedwith water and extracted with ethyl acetate (25 mL×2). The combinedorganic layer was washed with brine solution (25 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to get crudecompound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 10% ethyl acetate in pet-ether as mobilephase to give ethyl 1-methyl-4-oxo-5-phenylpiperidine-3-carboxylate (7.1g, 67%) as oily liquid. LC-MS (M+H)⁺=262.2.

Intermediate AF(3)

6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione

To a cooled solution of Intermediate AF(2) (4.5 g, 17.2 mmol) in ethanolwas added t-BuOK (4.8 g, 43.1 mmol) followed by urea (2.58 g, 43.1mmol). The reaction mixture was heated at reflux for 24 h. The reactionmass was quenched with water and evaporated the solvent under reducedpressure. The residue was diluted with water and extracted with ethylacetate (50 mL×3). The combined organic layer was washed with brinesolution (50 mL), dried over Na₂SO₄ and evaporated under reducedpressure to get crude compound. The crude compound was purified bycolumn chromatography (Silica gel, 60-120 mesh) using 10% methanol indichloromethane as mobile phase to give6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione(2.5 g, 56%) as pale yellow solid. LC-MS (M+H)⁺=258.2 ¹H NMR (400 MHz,DMSO-d6): δ ppm 11.04 (1H, s), 10.56 (1H, s), 7.33-7.23 (5H, m), 3.73(1H, m), 4.75 (1H, m), 2.83 (1H, m), 2.78 (1H, m), 2.68 (1H, m), 2.22(3H, s).

Preparation AF2,4-dichloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

A solution of Intermediate AF(3) (4.0 g, 15.56 mmol) and catalyticamount of DMF in POCl₃ (20 vol.) was heated at reflux for 10 h. Theexcess of POCl₃ was evaporated under reduced pressure. The residue waspoured in to crushed ice and stirred for 15 min. The aqueous solutionwas extracted with ethyl acetate (75 mL×3). The combined organic layerwas washed with aqueous saturated NaHCO₃ (50 mL×2), brine solution (75mL), dried over Na₂SO₄ and evaporated under reduced pressure to give2,4-dichloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine(1.2 g, 27%) as brown solid. LC-MS (M+H)⁺=294.0.

Preparation AFa2-chloro-N,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

To a solution of Preparation AF (1.0 g, 3.4 mmol) in acetonitrile wasadded diisopropylethylamine (1.3 g, 10.2 mmol) followed by addition ofmethylamine hydrochloride (0.34 g, 5.1 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified bycolumn chromatography (60-120 mesh) using 10% methanol indichloromethane as mobile phase to give2-chloro-N,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine(0.9 g, 91%) as off-white solid. LC-MS (M+H)⁺=289.2.

Preparation AFb2-chloro-N-ethyl-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

To a solution of Preparation AF (0.4 g, 1.36 mmol) in acetonitrile wasadded diisopropylethylamine (0.52 g, 4.0 mmol) followed by addition ofethylamine hydrochloride (0.16 g, 2.0 mmol) at room temperature. Thereaction mixture was stirred at the same temperature for 18 h. Thesolvent was removed under reduced pressure and the residue was purifiedby column chromatography (60-120 mesh) using 50% ethyl acetate inpet-ether as mobile phase to give2-chloro-N-ethyl-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine(0.4 g, 97%) as off-white solid. LC-MS (M−H)⁺=303.2.

Preparation AG2,4-dichloro-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Intermediate AG(1)

ethyl 2-cyano-2-(4-fluorophenyl)acetate

To a solution of sodium hydride (4.2 g, 177.7 mmol) in THF was added4-fluoro phenyl acetonitrile (10 g, 74.0 mmol) at −10° C. The reactionmixture was stirred for 15 min at the same temperature. Diethylcarbonate (10.5 g, 88.0 mmol) was added to the reaction mixture and thereaction mixture was allowed to come to room temperature and heated to40° C. (Caution: Reaction will start suddenly and exothermic). Theheating path was removed immediately once the reaction was started andthe reaction mixture was cooled under ice/acetone. The solution wasallowed to come to room temperature and stirred for 1 h. The reactionmass was cooled to 0° C. and quenched with aqueous saturated ammoniumchloride and extracted with ethyl acetate (50 mL×3). The combinedorganic layer was washed with water (50 mL), brine solution (50 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure togive ethyl 2-cyano-2-(4-fluorophenyl)acetate as crude compound as crudecompound (10 g). The crude compound was taken to the next step withoutfurther purification. LC-MS (M−H)⁺=206.2. ¹H NMR (400 MHz, CDCl₃) δ ppm7.44 (2H, m), 7.11 (2H, m), 4.69 (1H, s), 4.27-4.22 (2H, q, J=7.2 Hz).1.26 (3H, m)

Intermediate AG(2)

ethyl 3-amino-2-(4-fluorophenyl)propanoate

To a solution of Intermediate AG(1) (10.0 g, 40.0 mmol) in acetic acidwas added palladium on carbon (10%, w/w) followed by H₂SO₄ (0.5 vol., 5mL) at room temperature. The reaction mixture was hydrogenated under 5kg of hydrogen pressure for 18 h. The reaction mixture was filteredthrough celite bed and washed with methanol. The filtrate was evaporatedunder reduced pressure and the residue was neutralized with aqueoussaturated bicarbonate solution. The aqueous solution was extracted withethyl acetate (100 mL×4). The combined organic layer was washed withbrine solution (100 mL), dried over anhydrous Na₂SO₄ and evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by column chromatography (Silica gel, 60-120 mesh) using 10%methanol in dichloromethane as mobile phase to give ethyl3-amino-2-(4-fluorophenyl)propanoate (6.0 g, 59%) as oily liquid. LC-MS(M+H)⁺=212.2. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.26-7.22 (2H, m),7.04-6.98 (2H, m), 4.15 (2H, m), 3.66 (1H, m), 3.28 (1H, m), 2.99 (1H,m). 1.20 (3H, m).

Intermediate AG(3)

ethyl 3-(3-ethoxy-3-oxopropylamino)-2-(4-fluorophenyl)propanoate

To a solution of Intermediate AG(2) (3.0 g, 14.0 mmol) in ethanol wasadded ethyl acrylate (1.7 g, 17.0 mmol) at room temperature. Thereaction mixture was stirred at the same temperature for 18 h. Thesolvent was evaporated under reduced pressure and the crude compound waspurified by column chromatography (Silica gel, 60-120 mesh) using 50%ethyl acetate in pet-ether as mobile phase to give ethyl3-(3-ethoxy-3-oxopropylamino)-2-(4-fluorophenyl)propanoate (2.5 g, 60%)as yellowish oily liquid. LC-MS (M+H)⁺=313.2. ¹H NMR (400 MHz, CDCl₃): δppm 7.27-7.21 (2H, m), 7.03-6.97 (2H, m), 4.13 (4H, m), 3.77 (1H, m),3.23 (1H, m), 2.89 (3H, m), 2.48 (2H, m). 1.22 (6H, m).

Intermediate AG(4)

ethyl3-((3-ethoxy-3-oxopropyl)(4-methoxybenzyl)amino)-2-(4-fluorophenyl)propanoate

To a solution of Intermediate AG(3) (2.0 g, 6.42 mmol) in acetone wasadded K₂CO₃ (1.39 g, 9.6 mmol) followed by p-methoxybenzyl bromide (1.68g, 8.35 mmol) at room temperature. The reaction mixture was heated atreflux for 3 h. The solvent was removed under reduced pressure and theresidue was diluted with water. The aqueous layer was extracted withethyl acetate (25×2). The combined organic layer was washed with brinesolution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (Silica gel, 60-120 mesh) using 30% ethylacetate in pet-ether as mobile phase to give ethyl3-((3-ethoxy-3-oxopropyl)(4-methoxybenzyl)amino)-2-(4-fluorophenyl)propanoate(1.6 g, 60%) as oily liquid. LC-MS (M+H)⁺=432.2. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.22 (2H, m), 7.09, (2H, m), 6.95 (2H, m), 6.78 (2H, m)4.14 (4H, m), 3.80 (3H, s), 3.77 (2H, m), 3.53 (2H, m), 3.16 (1H, m),2.79 (2H, m), 2.43 (2H, m), 1.24 (6H, m).

Intermediate AG(5)

ethyl5-(4-fluorophenyl)-1-(4-methoxybenzyl)-4-oxopiperidine-3-carboxylate

To a cooled solution of Intermediate AG(4) (1.6 g, 3.71 mmol) in THF wasadded t-BuOK (0.62 g, 5.56 mmol). The reaction mixture was stirred atroom temperature for 2 h. The reaction mass was quenched with water thenevaporated the solvent under reduced pressure. The residue was dilutedwith water and extracted with ethyl acetate (25 mL×2). The combinedorganic layer was washed with brine solution (30 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to get crudecompound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 25% ethyl acetate in pet-ether as mobilephase to give ethyl5-(4-fluorophenyl)-1-(4-methoxybenzyl)-4-oxopiperidine-3-carboxylate(1.0 g, 70%) as oily liquid. LC-MS (M+H)⁺=386.2. ¹H NMR (400 MHz,CDCl₃): δ ppm 12.0 (1H, s) 7.26 (4H, m), 7.15 (2H, m), 6.88 (2H, m),4.15 (2H, m), 3.80 (3H, s), 3.77 (2H, m), 3.57 (2H, m), 2.80 (1H, m),2.40 (1H, m), 1.24 (3H, m).

Intermediate AG(6)

8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione

To a cooled solution of Intermediate AG(5) (1.0 g, 2.59 mmol) in ethanolwas added t-BuOK (0.436 g 3.89 mmol) followed by urea (0.233 g, 3.89mmol). The reaction mixture was heated at reflux for 24 h. The reactionmass was quenched with water and evaporated the solvent under reducedpressure. The residue was diluted with water and extracted with ethylacetate (25 mL×2). The combined organic layer was washed with brinesolution (30 mL), dried over Na₂SO₄ and evaporated under reducedpressure to get crude compound. The crude compound was purified bycolumn chromatography (Silica gel, 60-120 mesh) using 10% pet-ether inethyl acetate as mobile phase to give8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione(0.6 g, 63%) as pale yellow solid. LC-MS (M+H)⁺=382.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 11.06 (1H, s), 10.60 (1H, s), 7.35 (2H, m), 7.29 (2H,m), 7.05 (2H, m), 6.77 (2H, m), 4.05 (1H m), 3.75 (3H, s), 3.53 (1H, m),3.44 (2H, m), 2.88 (1H, m), 2.65 (2H, m).

Preparation AG2,4-dichloro-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

A solution of Intermediate AG(6) (0.6 g, 1.57 mmol) and catalytic amountof DMF in POCl₃ (20 vol.) was heated at reflux for 10 h. The excess ofPOCl₃ was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 min. The aqueous solution wasextracted with ethyl acetate (20 mL×3). The combined organic layer waswashed with aqueous saturated NaHCO₃ (10 mL×2), brine solution (10 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure togive2,4-dichloro-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine(0.35 g,) as brown solid. LC-MS (M+H)⁺=418.3.

Preparation AGa2-chloro-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-N-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

To a solution of Preparation AG (1.0 g, 2.39 mmol) in methanol was addeddiisopropylethylamine (0.62 g, 4.79 mmol) followed by methylaminehydrochloride (0.192 g, 2.87 mmol) at room temperature. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography (60-120 mesh) using 35% ethyl acetate in pet-ether asmobile phase to give2-chloro-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-N-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine(0.408 g, 41%) as off-white solid. LC-MS (M+H)⁺=413.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 7.32 (1H, m), 7.24-7.20 (2H, m), 7.14-7.06 (4H, m), 6.82(2H, m), 3.96 (1H, m), 3.72 (3H, s), 3.67 (1H, m), 3.59 (1H, m), 3.50(1H, m), 3.20 (1H, m), 2.82 (3H, d, J=4.0 Hz), 2.80 (1H, m), 2.51 (1H,m).

Preparation AGb2-chloro-N-ethyl-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

To a solution of Preparation AG (1.0 g, 2.39 mmol) in methanol was addeddiisopropylethylamine (0.61 g, 4.79 mmol) followed by ethylaminehydrochloride (0.23 g, 2.86 mmol) at room temperature. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography (60-120 mesh) using 30-35% ethyl acetate in pet-ether asmobile phase to give2-chloro-N-ethyl-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine(0.54 g, 54%) as off-white solid. LC-MS (M+H)⁺=427.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 7.32 (1H, m), 7.30-7.19 (2H, m), 7.13-7.05 (4H, m), 6.80(2H, m), 3.93 (1H, m), 3.71 (3H, s), 3.68-3.48 (5H, m), 3.22 (1H, m),2.80 (1H, m), 2.68 (1H, m), 1.15 (3H, m).

Preparation AGc2-chloro-N-ethyl-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-N-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

To a solution of Preparation AG (1.2 g, 2.87 mmol) in methanol was addeddiisopropylethylamine (0.74 g, 5.75 mmol) followed by ethylmethylamine(0.20 g, 3.44 mmol) at room temperature. The reaction mixture wasstirred at room temperature for 18 h. The solvent was removed underreduced pressure and the residue was purified by column chromatography(60-120 mesh) using 30-35% ethyl acetate in petroleum-ether as mobilephase to give2-chloro-N-ethyl-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-N-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine(0.50 g, 41%) as off-white solid. LC-MS (M+H)⁺=441.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 7.23-7.16 (4H, m), 7.11-7.07 (2H, m), 6.84 (2H, m), 4.10(1H, m), 3.73 (3H, s), 3.65-3.56 (3H, m), 3.51-3.40 (3H, m), 3.04 (1H,m), 2.99 (3H, s), 2.58 (1H, m), 1.11 (3H, t, J=7.0 Hz).

Preparation AGd2-chloro-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

To a solution of Preparation AG (0.75 g, 1.79 mmol) in methanol wasadded diisopropylethylamine (0.58 g, 4.49 mmol) followed by3,3-difluoroazetidine (0.25 g, 1.97 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified bycolumn chromatography (60-120 mesh) using 30% ethyl acetate in pet-etheras mobile phase to give2-chloro-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine(0.4 g, 48%) as off-white solid. LC-MS (M+H)⁺=475.2. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.25-7.10 (4H, m), 6.97-6.82 (2H, m), 6.80 (2H, m), 4.52(4H, m), 4.07 (1H, m), 3.80 (3H, s), 3.59 (3H, m), 3.36 (1H, m), 2.93(1H, m), 2.80 (1H, m).

Preparation AGeN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.215 g, 0.966 mmol), Preparation AGa (0.40g, 0.966 mmol), Na₂CO₃ (0.205 g, 1.93 mmol) and xantphos (0.558 g, 0.966mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.50 g, 0.48 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through celite bed and washed with ethyl acetate. Thefiltrate was evaporated under reduced pressure and the residue wasdiluted with water. The aqueous solution was extracted with ethylacetate (25 mL×3). The combined organic layer was washed with brinesolution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (Silica gel, 60-120 mesh) using 5% ethylacetate in dichloromethane as mobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.20 g, 35%) as off-white solid. LC-MS (M+H)⁺=600.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.09 (1H, s), 8.05 (1H, s), 7.72 (1H, s), 7.41 (1H, s),7.26-7.22 (2H, m), 7.14-7.05 (7H, m), 6.82-6.75 (2H, m), 3.93 (1H, m),3.76 (4H, m), 3.74 (2H, m), 3.72 (1H, m), 3.70 (3H, s), 2.92 (3H, d,J=4.0 Hz), 2.90 (1H, m), 2.70 (1H, m).

Preparation AGfN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.283 g, 1.26 mmol), Preparation AGb (0.54g, 1.26 mmol), Na₂CO₃ (0.26 g, 2.53 mmol) and xantphos (0.73 g, 1.26mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.65 g, 0.63 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through celite bed and washed with ethyl acetate. Thefiltrate was evaporated under reduced pressure and the residue wasdiluted with water. The aqueous solution was extracted with ethylacetate (50 mL×2). The combined organic layer was washed with brinesolution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (Silica gel, 60-120 mesh) using 7% ethylacetate in dichloromethane as mobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.22 g, 29%) as off-white solid. LC-MS (M+H)⁺=614.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.05 (1H, s), 7.97 (1H, s), 7.72 (1H, s), 7.41 (1H, s),7.39-7.29 (3H, m), 7.25-7.09 (6H, m), 6.81-6.75 (2H, m), 6.72 (1H, m),3.93 (1H, m), 3.71 (3H, s), 3.67 (1H, m), 3.57 (3H, s), 3.52 (1H, m),3.49 (2H, m), 3.24 (1H, m) 2.83 (1H, m), 2.65 (1H, m), 1.16 (3H, t,J=7.2 Hz).

Preparation AGgN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation B (0.275 g, 1.43 mmol), Preparation AGb (0.68g, 1.59 mmol), Na₂CO₃ (0.33 g, 3.19 mmol) and xantphos (0.92 g, 1.59mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.82 g, 0.79 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through celite bed and washed with ethyl acetate. Thefiltrate was evaporated under reduced pressure and the residue wasdiluted with water. The aqueous solution was extracted with ethylacetate (50 mL×2). The combined organic layer was washed with brinesolution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (Silica gel, 60-120 mesh) using 10% ethylacetate in dichloromethane as mobile phase to giveN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.6 g, 65%) as off-white solid. LC-MS (M+H)⁺=583.2.

Preparation AGhN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation C (0.20 g, 1.05 mmol), Preparation AGb (0.50g, 1.17 mmol), Na₂CO₃ (0.24 g, 2.34 mmol) and xantphos (0.67 g, 1.17mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.60 g, 0.58 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diatomaceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (25 mL×2). The combined organic layer waswashed with brine solution (20 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by column chromatography (Silica gel, 60-120 mesh)using 10% ethyl acetate in dichloromethane as mobile phase to giveN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.51 g, 73%) as off-white solid. LC-MS (M+H)⁺=583.2.

Preparation AGiN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.25 g, 1.13 mmol), Preparation AGc (0.50g, 1.13 mmol), Na₂CO₃ (0.24 g, 2.28 mmol) and xantphos (0.65 g, 1.14mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.60 g, 0.560 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through celite bed and washed with ethyl acetate. Thefiltrate was evaporated under reduced pressure and the residue wasdiluted with water. The aqueous solution was extracted with ethylacetate (20 mL×3). The combined organic layer was washed with brinesolution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (Silica gel, 60-120 mesh) using 5-10% ethylacetate in dichloromethane as mobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.45 g, 63%) as off-white solid. LC-MS (M+H)⁺=628.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.15 (1H, s), 7.86 (1H, s), 7.73 (1H, s), 7.42 (1H, s),7.24-7.21 (4H, m), 7.18-7.07 (4H, m), 6.86 (2H, m), 4.11 (1H, m), 3.70(3H, s), 3.65 (2H, m), 3.56 (3H, s), 3.47 (2H, m), 3.40 (2H, m), 3.07(1H, m), 2.98 (3H, s), 2.51 (1H, m), 1.24 (3H, t, J=7.2 Hz).

Preparation AGjN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of Preparation A (0.20 g, 0.92 mmol), Preparation AGd (0.40g, 0.84 mmol), Na₂CO₃ (0.18 g, 1.77 mmol) and xantphos (0.48 g, 0.84mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.43 g, 0.420 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through celite bed and washed with ethyl acetate. The filtratewas evaporated under reduced pressure and the residue was diluted withwater. The aqueous solution was extracted with ethyl acetate (25 mL×3).The combined organic layer was washed with brine solution (25 mL), driedover anhydrous Na₂SO₄ and evaporated under reduced pressure to get crudecompound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 5% ethyl acetate in dichloromethane asmobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine(0.25 g, 49%) as off-white solid. LC-MS (M+H)⁺=663.0.

Preparation AGkN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AGe (0.20 g, 0.330 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (25 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (25mL×3). The combined organic layer was washed with brine solution (25mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.08 g, 51%) as crude compound. The crude compound was taken to thenext step without further purification. LC-MS (M+H)⁺=480.2. ¹H NMR (400MHz, DMSO-d6): δ ppm 9.36 (1H, s), 7.86 (1H, s), 7.75 (1H, s), 7.43 (1H,s), 7.32-7.28 (3H, m), 7.23-7.11 (4H, m), 4.30 (1H, m), 4.02 (1H, m),3.98 (1H, m), 3.71 (1H, m), 3.56 (3H, s), 3.38 (1H, m), 2.98 (3H, d,J=4.0 Hz).

Preparation AGl (BBRC-7610)N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AGf (0.22 g, 0.35 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (25 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (50mL×3). The combined organic layer was washed with brine solution (25mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamineas crude compound (0.16 g, 93%). The crude compound was taken to thenext step without further purification. LC-MS (M+H)⁺=494.2. ¹H NMR (400MHz, DMSO-d6): δ ppm 9.01 (1H, s), 7.98 (1H, s), 7.72 (1H, s), 7.41 (1H,s), 7.21-7.17 (2H, m), 7.13-7.05 (4H, m), 6.67 (1H, m), 3.82 (1H, m),3.66 (2H, m), 3.56 (3H, s), 3.50 (2H, m), 3.20 (1H, m), 2.85 (1H, m),1.20 (3H, t, J=7.2 Hz).

Preparation AGmN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AGg (0.40 g, 0.68 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (20 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (25mL×3). The combined organic layer was washed with brine solution (25mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.30 g, 94%) as crude compound. The crude compound was taken to thenext step without further purification. LC-MS (M+H)⁺=463.2. ¹H NMR (400MHz, DMSO-d6): δ ppm 9.29 (1H, s), 8.68 (1H, s), 8.03 (1H, m), 7.44-7.37(2H, m), 7.25-7.21 (2H, m), 7.12-7.07 (2H, m), 6.76 (1H, m), 3.83 (1H,m), 3.68-3.60 (2H, m), 3.55-3.46 (2H, m), 3.22 (1H, m), 2.91 (1H, m),2.34 (3H, s), 1.20 (3H, t, J=7.2 Hz).

Preparation AGnN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AGh (0.51 g, 0.87 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (25 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (25mL×3). The combined organic layer was washed with brine solution (25mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.31 g, 78%) as crude compound. The crude compound was taken to thenext step without further purification. LC-MS (M+H)⁺=463.2. ¹H NMR (400MHz, DMSO-d6): δ ppm 9.29 (1H, s), 8.68 (1H, s), 8.02 (1H, m), 7.42 (2H,m), 7.23 (2H, m), 7.28-7.10 (2H, m), 6.75 (1H, m), 3.80 (1H, m),3.67-3.60 (2H, m), 3.55-3.48 (2H, m), 3.22 (1H, m), 2.89 (1H, m), 2.34(3H, s), 1.24 (3H, t, J=7.0 Hz).

Preparation AGo(BBRC-4363)N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AGi (0.10 g, 0.15 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (10 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (20mL×3). The combined organic layer was washed with brine solution (25mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.03 g) as crude compound. The crude compound was taken to the nextstep without further purification. LC-MS (M+H)⁺=508.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 7.78 (1H, s), 7.77 (1H, s), 7.37 (1H, s), 7.20-7.16 (3H,m), 7.12-7.06 (4H, m), 4.04 (2H, m), 3.80 (1H, m), 3.50 (3H, s),3.42-3.32 (3H, m), 3.15 (3H, s), 2.81 (1H, m), 1.17 (3H, t, J=7.2 Hz).

Preparation AGp (BBRC-4364)N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

To a solution of Preparation AGj (0.20 g, 0.30 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (10 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (25mL×3). The combined organic layer was washed with brine solution (50mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine(0.12 g, 70%) as crude compound. The crude compound was taken to thenext step without further purification. LC-MS (M+H)⁺=542.0. ¹H NMR (400MHz, DMSO-d6): δ ppm 9.31 (1H, s), 7.87 (1H, s), 7.73 (1H, s), 7.41 (1H,s), 7.22 (2H, m), 7.15-7.07 (4H, m), 4.74-4.59 (4H, m), 3.97 (1H, m),3.87 (1H, m), 3.76 (1H, m), 3.51 (3H, s), 3.27 (1H, m), 2.83 (1H, m).

Preparation AH2,4-dichloro-8-(4-fluorophenyl)-6-methy-1-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Intermediate AH(1)

ethyl3-((3-ethoxy-3-oxopropyl)(4-methoxybenzyl)amino)-2-(4-fluorophenyl)propanoate

To a solution of Intermediate AG(3) (12.0 g, 38.5 mmol) in acetone wasadded K₂CO₃ (6.38 g, 46.3 mmol) followed by methyl iodide (6.5 g, 46.3mmol) at 0° C. The reaction mixture was stirred at room temperature for2 h. The solvent was removed under reduced pressure and the residue wasdiluted with water. The aqueous layer was extracted with ethyl acetate(50×3). The combined organic layer was washed with brine solution (75mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto get crude compound. The crude compound was purified by columnchromatography (Silica gel, 60-120 mesh) using 20% ethyl acetate inpet-ether as mobile phase to give ethyl3-((3-ethoxy-3-oxopropyl)(methyl)amino)-2-phenylpropanoate (6.0 g, 50%)as oily liquid. LC-MS (M+H)⁺=326.2. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.01(2H, m), 6.98, (2H, m), 4.16-4.07 (4H, m), 3.77 (1H, m), 3.13 (1H, t,J=2.4 Hz), 2.75-2.51 (5H, m), 2.17 (3H, s), 1.26-1.19 (6H, m).

Intermediate AH(2)

ethyl 5-(4-fluorophenyl)-1-methyl-4-oxopiperidine-3-carboxylate

To a cooled solution of Intermediate AH(1) (6.0 g, 18.4 mmol) in THF wasadded t-BuOK (4.1 g, 36.9 mmol). The reaction mixture was stirred atroom temperature for 2 h. The reaction mass was quenched with water thenevaporated the solvent under reduced pressure. The residue was dilutedwith water and extracted with ethyl acetate (25 mL×4). The combinedorganic layer was washed with brine solution (30 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to get crudecompound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 20% ethyl acetate in pet-ether as mobilephase to give ethyl5-(4-fluorophenyl)-1-methyl-4-oxopiperidine-3-carboxylate (3.0 g, 51%)as oily liquid. LC-MS (M+H)⁺=278.2. ¹H NMR (400 MHz, DMSO-d6): δ ppm7.35 (1H, m), 7.15 (1H, m), 7.12 (1H, m), 6.98 (1H, m), 4.01 (2H, m),3.88 (1H, m), 2.60 (1H, m), 2.38 (2H, m), 2.19 (3H, s), 1.19-1.08 (3H,m).

Intermediate AH(3)

8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione

To a cooled solution of Intermediate AH(2) (3.0 g, 10.75 mmol) inethanol was added t-BuOK (3.0 g 26.8 mmol) followed by urea (1.6 g, 26.8mmol). The reaction mixture was heated at reflux for 36 h. The reactionmass was quenched with water and evaporated the solvent under reducedpressure. The residue was diluted with water and extracted with ethylacetate (25 mL×3). The combined organic layer was washed with brinesolution (30 mL), dried over Na₂SO₄ and evaporated under reducedpressure to get crude compound. The crude compound was purified bycolumn chromatography (Silica gel, 60-120 mesh) using 100% ethyl acetateas mobile phase to give8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione(1.5 g, 51%) as pale yellow solid. LC-MS (M+H)⁺=276.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 11.08 (1H, s), 10.59 (1H, s), 7.31 (2H, m), 7.13 (2H,m), 3.74 (1H, m), 3.17 (1H, m), 2.80-2.59 (2H, m), 2.23 (3H, s).

Preparation AH2,4-dichloro-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

A solution of Intermediate AH(3) (1.5 g, 5.45 mmol) and catalytic amountof DMF in POCl₃ (20 vol.) was heated at reflux for 10 h. The excess ofPOCl₃ was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 min. The aqueous solution wasextracted with ethyl acetate (20 mL×2). The combined organic layer waswashed with aqueous saturated NaHCO₃ (10 mL×2), brine solution (10 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure togive2,4-dichloro-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine(0.7 g, 56%) as brown solid. LC-MS (M+H)⁺=312.2.

Preparation AHa2-chloro-8-(4-fluorophenyl)-N,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

To a solution of Preparation AH (0.4 g, 1.28 mmol) in methanol was addeddiisopropylethylamine (0.33 g, 2.57 mmol) followed by methylaminehydrochloride (0.16 g, 2.57 mmol) at room temperature. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography (60-120 mesh) using 50% ethyl acetate in pet-ether asmobile phase to give2-chloro-8-(4-fluorophenyl)-N,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine(0.20 g, 51.2%) as off-white solid. LC-MS (M+H)⁺=307.2.

Preparation AHb2-chloro-N-ethyl-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

To a solution of Preparation AH (0.7 g, 2.25 mmol) in methanol was addeddiisopropylethylamine (0.58 g, 4.50 mmol) followed by ethylaminehydrochloride (0.4 g, 4.50 mmol) at room temperature. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography (60-120 mesh) using 30-35% ethyl acetate in pet-ether asmobile phase to give2-chloro-N-ethyl-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine(0.21 g, 29%) as off-white solid. LC-MS (M+H)⁺=321.2.

Preparation AHc2-chloro-N-ethyl-8-(4-fluorophenyl)-N,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

To a solution of Preparation AH (0.35 g, 1.1 mmol) in methanol was addeddiisopropylethylamine (0.29 g, 2.2 mmol) followed by ethylmethylamine(0.67 g, 1.35 mmol) at room temperature. The reaction mixture wasstirred at room temperature for 18 h. The solvent was removed underreduced pressure and the residue was purified by column chromatography(60-120 mesh) using 35% ethyl acetate in pet-ether as mobile phase togive2-chloro-N-ethyl-8-(4-fluorophenyl)-N,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine(0.22 g, 58%) as off-white solid. LC-MS (M+H)⁺=333.9.

Preparation AI2,4-dichloro-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Intermediate AI(1)

ethyl 2-amino-2-(4-fluorophenyl)acetate

To a cooled solution of 2-amino-2-(4-fluorophenyl)acetic acid (1.0 g,6.17 mmol) in ethanol was added con. H₂SO₄ (1 mL) over a period of 1min. The reaction mixture was heated at reflux for 5 h. The solvent wasevaporated under reduced pressure and the residue was diluted with ethylacetate (20 mL). The organic solution was washed with aqueous saturatedNaHCO₃ (15 mL×2), water (20 mL), brine solution (10 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to give ethyl2-amino-2-(4-fluorophenyl)acetate (0.75 g, 65%) as crude compound (oilyliquid). The crude compound was taken to the next step without furtherpurification. LC-MS (M+H₂O)⁺=198.0. ¹H NMR (400 MHz, DMSO-d6): δ7.44-7.40 (2H, m), 7.18-7.13 (2H, m), 4.51 (1H, s), 4.12-4.01 (2H, m),2.26 (2H, s), 1.12 (3H, t, J=8.0 Hz).

Intermediate AI(2)

ethyl 4-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethylamino)butanoate

To a solution of Intermediate AI(1) (4.2 g, 21.3 mmol) in DMF was addedcesium carbonate (8.3 g, 2.25 mmol) followed ethyl 4-bromobutyroate(4.98 g, 2.55 mmol) at room temperature. The reaction mixture wasstirred at 70° C. for 18 h. The solvent was evaporated under reducedpressure and the crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 25% ethyl acetate in pet-ether as mobilephase to give ethyl4-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethylamino)butanoate (2.0 g, 30%) asyellowish oily liquid. LC-MS (M+H)⁺=312.2. ¹H NMR (400 MHz, CDCl₃): δppm 7.33 (2H, m), 7.06 (2H, m), 4.31 (1H, m), 4.18 (4H, m), 2.63 (1H,m), 2.49 (1H, m), 2.35 (2H, m), 1.81 (1H, m), 1.24 (6H, m).

Intermediate AI(3)

ethyl 4-((2-ethoxy-1-(4-fluorophenyl)-2-oxoethyl)(4-methoxybenzyl)amino)butano ate

To a solution Intermediate AI(2) (15.0 g, 48.23 mmol) in acetone wasadded K₂CO₃ (7.9 g, 57.8 mmol) followed by 4-methoxybenzyl bromide (14.5g, 72.3 mmol) at 0° C. The reaction mixture was heated at 70° C. for 18h. The solvent was removed under reduced pressure and the residue wasdiluted with water. The aqueous layer was extracted with ethyl acetate(100×2). The combined organic layer was washed with brine solution (75mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto get crude compound. The crude compound was purified by columnchromatography (Silica gel, 60-120 mesh) using 30% ethyl acetate inpet-ether as mobile phase to give ethyl4-((2-ethoxy-1-(4-fluorophenyl)-2-oxoethyl)(4-methoxybenzyl)amino)butanoate(12.0 g, 60%) as oily liquid. LC-MS (M+H)⁺432.2. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.30 (2H, m), 7.22 (2H, m), 7.01 (2H, m), 6.99 (2H, m),4.52 (1H, s), 4.22 (2H, m), 4.04 (2H, m), 3.79 (5H, m), 3.61 (1H, m),2.71 (1H, m), 2.57 (1H, m), 2.20 (1H, m), 2.07 (1H, m), 1.70 (2H, m),1.28 (3H, m, J=7.2 Hz), 1.20 (3H, m, J=7.2 Hz).

Intermediate AI(4)

ethyl2-(4-fluorophenyl)-1-(4-methoxybenzyl)-3-oxopiperidine-4-carboxylate

To a cooled solution of Intermediate AI(3) (12.0 g, 27.7 mmol) in THFwas added t-BuOK (6.2 g, 55.5 mmol). The reaction mixture was stirred atroom temperature for 3 h. The reaction mass was quenched with water thenevaporated the solvent under reduced pressure. The residue was dilutedwith water and extracted with ethyl acetate (50 mL×4). The combinedorganic layer was washed with brine solution (50 mL), dried overanhydrous Na₂SO₄ and evaporated under reduced pressure to get crudecompound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 20% ethyl acetate in pet-ether as mobilephase to give ethyl2-(4-fluorophenyl)-1-(4-methoxybenzyl)-3-oxopiperidine-4-carboxylate(7.0 g, 67%) as oily liquid. LC-MS (M+H)⁺=386.2. ¹H NMR (400 MHz,CDCl₃): δ ppm 12.02 (1H, s), 7.43 (2H, m), 7.15 (2H, m), 7.04 (2H, m),6.84 (2H, m), 4.23 (2H, q, J=7.2 Hz), 4.05 (1H, s), 3.79 (3H, s), 3.65(1H, d, J=13.6 Hz), 3.22 (1H, d, J=13.6 Hz), 2.92 (1H, m), 2.35 (3H, m),1.32 (3H, t, J=7.2 Hz).

Intermediate AI(5)

8-(4-fluorophenyl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione

To a cooled solution of Intermediate AI(4) (7.0 g, 18.1 mmol) in ethanolwas added t-BuOK (5.0 g 45.4 mmol) followed by urea (2.7 g, 45.4 mmol).The reaction mixture was heated at reflux for 18 h. The reaction masswas quenched with water and evaporated the solvent under reducedpressure. The residue was diluted with water and extracted with ethylacetate (50 mL×3). The combined organic layer was washed with brinesolution (75 mL), dried over Na₂SO₄ and evaporated under reducedpressure to get crude compound. The crude compound was purified bycolumn chromatography (Silica gel, 60-120 mesh) using 50% pet-ether inethyl acetate as mobile phase to give8-(4-fluorophenyl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione(3.0 g, 45%) as pale yellow solid. LC-MS (M+H)⁺=382.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 11.08 (1H, s), 10.44 (1H, s), 7.26-7.17 (6H, m), 6.92(2H, m), 4.36 (1H, s), 3.75 (3H, s), 3.73 (1H, d, J=13.2 Hz) 3.58 (1H,d, J=13.2 Hz), 2.63 (2H, m), 2.51 (1H, m), 2.35 (1H, m).

Preparation AI2,4-dichloro-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A solution of Intermediate AI(5) (2.0 g, 5.24 mmol) and catalytic amountof DMF in POCl₃ (30 vol.) was heated at 85° C. for 18 h. The excess ofPOCl₃ was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 min. The aqueous solution wasextracted with ethyl acetate (20 mL×3). The combined organic layer waswashed with aqueous saturated NaHCO₃ (10 mL×4), brine solution (25 mL),dried over anhydrous Na₂SO₄ and evaporated under reduced pressure togive2,4-dichloro-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(1.4 g, crude) as brown solid. LC-MS (M+H)⁺=418.0.

Preparation AIa2-chloro-N-ethyl-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

To a solution of Preparation AI (0.7 g, 1.67 mmol) in methanol was addeddiisopropylethylamine (0.43 g, 3.35 mmol) followed by ethylaminehydrochloride (0.27 g, 3.35 mmol) at room temperature. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography (60-120 mesh) using 35% ethyl acetate in pet-ether asmobile phase to givechloro-N-ethyl-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(0.36 g, 50%) as off-white solid. LC-MS (M+H)⁺=427.2. ¹H NMR: (400 MHz,DMSO-d6): δ ppm 7.38 (2H, m), 7.30 (2H, m), 7.20-7.13 (4H, m), 6.88 (2H,m), 4.45 (1H, s), 3.73 (3H, s), 3.45 (1H, m), 3.40-3.34 (3H, m), 2.88(1H, m), 2.42 (2H, m), 1.16 (3H, t, J=7.2 Hz).

Preparation AIb2-chloro-N-ethyl-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-N-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

To a solution of Preparation AI (0.7 g, 1.67 mmol) in methanol was addeddiisopropylethylamine (0.43 g, 3.3 mmol) followed by ethylmethylamineHCl (0.19 g, 3.35 mmol) at room temperature. The reaction mixture wasstirred at room temperature for 18 h. The solvent was removed underreduced pressure and the residue was purified by column chromatography(60-120 mesh) using 20% ethyl acetate in pet-ether as mobile phase togive2-chloro-N-ethyl-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-N-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(0.40 g, 54%) as off-white solid. LC-MS (M+H)⁺=441.2. ¹H NMR: (400 MHz,DMSO-d6) δ ppm 7.49 (2H, m), 7.19-7.14 (4H, m), 6.87 (2H, m), 4.42 (1H,s), 3.73 (3H, s), 3.55 (2H, m), 3.42 (1H, m), 3.21 (1H, m), 3.04 (3H,s), 2.95 (2H, m), 2.56 (1H, m), 2.25 (1H, m), 1.16 (3H, t, J=7.2 Hz).

Preparation AIc1 and AIc22-chloro-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a solution of Preparation AI (0.70 g, 1.6 mmol) in methanol was addeddiisopropylethylamine (0.40 g, 3.35 mmol) followed by(S)-3-fluoropyrrolidine (0.25 g, 2.14 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified bypep-HPLC to give2-chloro-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(0.150 g, 37% & 190 mg, 43%).

AIc1: LC-MS (M+H)⁺=471.1. ¹H NMR (400 MHz, chloroform-d): δ ppm 7.48(2H, m), 7.15 (2H, m), 7.01 (2H, m), 6.83 (2H, m), 5.30 (1H, m), 4.43(1H, s), 3.97-3.90 (4H, m), 3.88-3.72 (4H, m), 3.65 (1H, m), 3.17 (1H,m), 3.02 (2H, m), 2.33 (2H, m), 1.95 (1H, m).

AIc2: LC-MS (M+H)⁺=471.1. ¹H NMR (400 MHz, chloroform-d): δ ppm 7.28(2H, m), 7.18 (2H, m), 6.99 (2H, m), 6.84 (2H, m), 5.30 (1H, m), 4.58(1H, s), 4.20-4.11 (2H, m), 3.97-3.80 (6H, m), 3.69 (1H, m), 3.35 (1H,m), 2.88 (2H, m), 2.35 (1H, m), 2.17 (1H, m), 2.05 (1H, m).

Preparation AId2-chloro-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a solution of Preparation AI (0.70 g, 1.6 mmol) in methanol was addeddiisopropylethylamine (0.43 g, 3.35 mmol) followed by(R)-3-fluoropyrrolidine (0.25 g, 2.2 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. The solventwas removed under reduced pressure and the residue was purified bypep-HPLC to give2-chloro-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(0.150 g, 37% & 190 mg, 43%). LC-MS (M+H)⁺=471.2.

Preparation AIeN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.36 g, 0.845 mmol), Preparation Ma (0.189g, 0.845 mmol), Na₂CO₃ (0.179 g, 1.69 mmol) and xantphos (0.488 g, 0.845mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.870 g, 0.845 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through celite bed and washed with ethyl acetate. Thefiltrate was evaporated under reduced pressure and the residue wasdiluted with water. The aqueous solution was extracted with ethylacetate (50 mL×3). The combined organic layer was washed with brinesolution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (60-120 mesh) using 20% ethyl acetate inpet-ether as mobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine(0.30 g, 58%) as off-white solid. LC-MS (M+H)⁺=614.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 8.96 (1H, s), 7.79 (1H, s), 7.74 (1H, s), 7.43 (1H, s),7.33 (2H, m), 7.20 (6H, m), 6.89 (2H, m), 6.80 (1H, m), 4.44 (1H, s),3.74 (3H, s), 3.66 (3H, s), 3.50 (4, m), 2.90 (1H, m), 2.33 (3H, m),1.24 (3H, t, J=7.2 Hz).

Preparation AIfN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-N4-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.20 g, 0.90 mmol), Preparation AIb (0.41g, 0.90 mmol), Na₂CO₃ (0.192 g, 1.80 mmol) and xantphos (0.525 g, 0.90mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.470 g, 0.45 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through celite bed and washed with ethyl acetate. Thefiltrate was evaporated under reduced pressure and the residue wasdiluted with water. The aqueous solution was extracted with ethylacetate (50 mL×3). The combined organic layer was washed with brinesolution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (60-120 mesh) using 30% ethyl acetate inpet-ether as mobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-N4-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine(0.34 g, 59%) as off-white solid. This compound was taken to the nextstep without further analysis. LC-MS (M+H)⁺=628.2.

Preparation AIgN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

A solution of Preparation A (0.070 g, 0.319 mmol), Preparation AIc1(0.150 g, 0.319 mmol), Na₂CO₃ (0.067 g, 0.63 mmol) and xantphos (0.184g, 0.319 mmol) in dioxane/water (9:1) was purged with argon for 1 h atroom temperature. Pd(dba)₃ (0.165 g, 0.159 mmol) was added to thereaction mixture and the resulting solution was purged with argon foranother 1 h. The reaction mass was heated at 110° C. for 24 h. Thereaction mass was filtered through a bed of diatomaceous earth (Celite®)and washed with ethyl acetate. The filtrate was evaporated under reducedpressure and the residue was diluted with water. The aqueous solutionwas extracted with ethyl acetate (20 mL×3). The combined organic layerwas washed with brine solution (20 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by column chromatography (60-120 mesh) using 50%ethyl acetate in pet-ether as mobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine(0.1 g, 48%) as off-white solid. LC-MS (M+H)⁺=658.2.

Preparation AIhN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

A solution of Preparation A (0.09 g, 0.404 mmol), Preparation AIc2(0.190 g, 0.404 mmol), Na₂CO₃ (0.085 g, 0.80 mmol) and xantphos (0.230g, 0.404 mmol) in dioxane/water (9:1) was purged with argon for 1 h atroom temperature. Pd(dba)₃ (0.209 g, 0.202 mmol) was added to thereaction mixture and the resulting solution was purged with argon foranother 1 h. The reaction mass was heated at 110° C. for 24 h. Thereaction mass was filtered through a bed of diatomaceous earth (Celite®)and washed with ethyl acetate. The filtrate was evaporated under reducedpressure and the residue was diluted with water. The aqueous solutionwas extracted with ethyl acetate (20 mL×3). The combined organic layerwas washed with brine solution (20 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by column chromatography (60-120 mesh) using 50%ethyl acetate in pet-ether as mobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine(0.120 g, 48%) as off-white solid. LC-MS (M+H)⁺=538.2.

Preparation AIkN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

To a solution of Preparation AIe (0.30 g, 0.489 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (25 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (50mL×2). The combined organic layer was washed with brine solution (50mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamineas crude compound (0.20 g). The crude compound was taken to the nextstep without further purification. LC-MS (M+H)⁺=494.2.

Preparation AIl (Example 1)N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

To a solution of Preparation AIf (0.340 g, 0.541 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (10 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (20mL×3). The combined organic layer was washed with brine solution (25mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamineas crude compound (0.20 g). The crude compound was taken to the nextstep without further purification. LC-MS (M+H)⁺=508.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.05 (1H, s), 7.78 (1H, s), 7.74 (1H, s), 7.43 (1H, s),7.32 (2H, m), 7.21-7.0 (5H, m), 4.85 (1H, s), 3.59 (3H, s), 3.49 (2H,m), 3.05 (3H, s), 2.68 (2H, m), 2.51 (2H, m), 1.22 (3H, t, J=7.2 Hz).

Preparation AImN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

To a solution of Intermediate AIg (0.120 g, 0.182 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (10 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (20mL×2). The combined organic layer was washed with brine solution (25mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine(0.040 g, 50%). LC-MS (M+H)⁺=538.2.

Preparation AInN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5.6.7.8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

To a solution of Preparation AIh (0.120 g, 0.182 mmol) in toluene wasadded trifluoromethanesulfonic acid (3.0 vol.) at room temperature. Thereaction mixture was heated at reflux for 1 h. The solvent was removedunder reduced pressure and the residue was diluted with water. Theaqueous solution was washed with dichloromethane (10 mL×2), basified byusing aqueous saturated NaHCO₃ and extracted with ethyl acetate (20mL×2). The combined organic layer was washed with brine solution (20mL), dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine(0.045 g, 51%). LC-MS (M+H)⁺=538.2.

Preparation AJ2-chloro-4-(methylamino)-8-phenyl-7,8-dihydroquinazolin-8-ol

Intermediate AJ(1)

methyl 2-chloro-6-(methylamino)pyrimidine-4-carboxylate

To a mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (2 g),methylamine hydrochloride (0.72 g) in CH₂Cl₂ (48 mL) at 0° C. was addedHunig's base (3.7 mL) dropwise, and the reaction mixture was stirred atice bath for 1 h and then rt for 1 h. The solvent was removed in vacuo,and the white residue was purified directly by Biotage eluting with40-600% EtOAc/Hexanes (1000 mL) followed by 90% CH2Cl2/10% MeOH (4 L) togive the title compound as a white solid (1.8 g). These fractions werecombined and evaporated in vacuo. During the solvent removal, some whitesolid was formed. Several filtrations gave the title compound as a whitesolid (1.8 g, very white solid). LC-MS (M+H)⁺=202.00

Intermediate AJ(2)

2-chloro-N-methoxy-N-methyl-6-(methylamino)pyrimidine-4-carboxamide

To a suspension of methyl2-chloro-6-(methylamino)pyrimidine-4-carboxylate (1.95 g) andN,O-dimethylhydroxylamine hydrochloride (1.887 g, 19.34 mmol) in THF at−20° C. was added isopropylmagnesium chloride (23.60 mL, 47.2 mmol)dropwise through a dropping funnel over a period of 30 min, and thereaction mixture was stirred at −10° C. for 40 min. The reaction wasworked up with sat. NH₄Cl and EtOAc, and the crude product was purifiedby Biotage eluting with 40-90% EtOAc/Hexanes to give the title compoundas a colorless oil (786 mg). LC-MS (M+H)⁺=231.01.

Intermediate AJ(3)

5-bromo-2-chloro-N-methoxy-N-methyl-6-(methylamino)pyrimidine-4-carboxamide

To a solution of2-chloro-N-methoxy-N-methyl-6-(methylamino)pyrimidine-4-carboxamide (959mg) in MeCN (21 mL) was added NBS (814 mg), and the reaction mixture washeated at 60° C. for 8 h. The solvent was removed, and the residue waspurified by Biotage eluting with 50%-70 EtOAc/Hexanes (1.2 L) to givethe title compound as a white solid (1.1 g). LC-MS (M+H)⁺=310.95.

Intermediate AJ(4)

2-chloro-N-methoxy-N-methyl-6-(methylamino)-5-vinylpyrimidine-4-carboxamide

A solution of5-bromo-2-chloro-N-methoxy-N-methyl-6-(methylamino)pyrimidine-4-carboxamide(100 mg), tributyl(vinyl)stannane (113 mg), tetrakis (23 mg) in toluene(1.6 mL) was heated at 95° C. for 12 h, and the solvent was removed. Theresidue was purified by preparative TLC eluting with 50% EtOAc/Hexanesto give the title compound as a colorless oil (23 mg). LC-MS(M+H)⁺=257.06.

Intermediate AJ(5)

(2-chloro-6-(methylamino)-5-vinylpyrimidin-4-yl)(phenyl)methanone

To a solution of2-chloro-N-methoxy-N-methyl-6-(methylamino)-5-vinylpyrimidine-4-carboxamide(136 mg) in THF (1.8 mL) at 0° C. was added phenylmagnesium bromide (1 Msolution in THF, 1.3 mL)) dropwise, and the reaction mixture was stirredat 0° C. for 30 min. The reaction was worked up with EtOAc/sat. NH₄Cl,and the crude product was purified by preparative TLC eluting with 40%EtOAc/Hexanes to give the title compound as a colorless oil (87 mg).LC-MS (M+H)⁺=274.03.

Intermediate AJ(6)

1-(2-chloro-6-(methylamino)-5-vinylpyrimidin-4-yl)-1-phenylbut-3-en-1-ol

To a solution of(2-chloro-6-(methylamino)-5-vinylpyrimidin-4-yl)(phenyl)methanone (142mg) in THF (2.6 mL) at rt was added allylmagnesium bromide (1.0 Msolution in THF, 1.1 mL) dropwise, and the reaction mixture was stirredat rt for 30 min. The reaction was worked up with EtOAc/sat. NH₄Cl, andthe crude product was purified by prep. TLC eluting with 30%EtOAc/Hexanes to give the title compound as a colorless oil (133 mg).LC-MS (M−H₂O+H)⁺=298.18.

Preparation AJ2-chloro-4-(methylamino)-8-phenyl-7,8-dihydroquinazolin-8-ol

To a solution of1-(2-chloro-6-(methylamino)-5-vinylpyrimidin-4-yl)-1-phenylbut-3-en-1-ol(60 mg) in benzene (5 mL) was added Grubbs I (16 mg), and the reactionmixture was heated at 85° C. for 1 h. The solvent was removed, and theresidue was purified by preparative TLC eluting with 40% EtOAc/Hexanesto give the title compound as a colorless oil (50 mg). ¹H NMR (500 MHz,CDCl₃) δ ppm 7.4 (5H, m), 6.25 (1H, m), 6.07 (1H, m), 5.14 (1H, br. S),4.52 (1H, s), 3.10 (3H, d<J=5.0 Hz), 2.99 (2H, m). ¹³C NMR (125 MHz,CDCl₃) 164.32, 159.38, 158.85, 144.15, 128.24, 128.02, 127.83, 125.51,117.54, 108.14, 60.51, 38.50, and 28.57. HRMS calcd. for C₁₅FH₁₅ClN₃O(M+H) 288.0904; found: 288.0899.

Preparation AK2-chloro-4-(methylamino)-8-phenyl-5,6,7,8-tetrahydroquinazolin-8-ol

To a solution of2-chloro-4-(methylamino)-8-phenyl-7,8-dihydroquinazolin-8-ol (20 mg) inEtOAc (5 mL) was added 5% Pd/C (6 mg), and the resulting suspension wasstirred under a hydrogen balloon for 1 h. The reaction mixture wasfiltered through a pad of Celite to give the title compound as acolorless oil (20 mg).

¹H NMR (500 MHz, CDCl₃) δ ppm 7.3 (5H, m), 4.9 (1H, br. S), 4.02 (1H,s), 3.14 (3H, br. S), 1.5-2.5 (6H, m) ¹³C NMR (125 MHz, CDCl₃) 164.82,162.72, 158.56, 146.54, 128.02, 127.37, 126.72, 110.92, 74.81, 37.58,28.61, 21.89, 17.47. HRMS calcd. for C₁₅FH₁₇ClN₃O (M+H) 290.1060; found:290.1052.

Preparation AL2-chloro-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol

2-chloro-4-(dimethylamino)-7-phenyl-7H-cyclopenta[d]pyrimidin-7-ol wasprepared from methyl 2,6-dichloropyrimidine-4-carboxylate using the sametransformations as shown in Preparation AJ/AK with the followingdifferences: Intermediate AL(1): dimethylamine was used instead ofmethylamine hydrochloride, and 1.1 equiv of Hünig's base was used;Intermediate AL(6): vinylmagnesium bromide was used instead ofallylmagnesium bromide. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.3 (5H, m), 3.28(6H, s), 1.5-3.4 (5H, m). ¹³C NMR (125 MHz, CDCl₃) 174.66, 161.76,159.58, 144.61, 128.49, 127.58, 125.35, 113.92, 82.86, 41.07, 39.00,28.59. HRMS calcd. for C₁₅H₁₇ClN₃O (M+H) 290.1060; found: 290.1050.

Preparation AM (6S,7S)-2-chloro-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-6-ol

Intermediate AM(1)

2-chloro-N,N-dimethyl-7-phenyl-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of2-chloro-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol(85 mg) in i-PrOH (5 mL) was added HCl in ether (1M solution), and thereaction mixture was heated at 80° C. from 3 h. The solution was cloudyand turned to clear yellow solution by the end of the reaction. Thesolvents were removed, and the reaction mixture was worked up with EtOAcand saturated NaHCO₃ to give the title compound as a brownish solid (50mg). LC-MS (M−H₂O+H)⁺=272.07.

Preparation AM(6S,7S)-2-chloro-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-6-ol

To a solution of2-chloro-N,N-dimethyl-7-phenyl-5H-cyclopenta[d]pyrimidin-4-amine (113mg) in THF (2 mL) at rt was added borane dimethyl sulfide complex in THF(2.0 M solution, 0.41 mL), and the reaction mixture was stirred at rtfor 5 h. Water (0.50 mL) was added carefully, followed by 30% H₂O₂ (0.50mL) and 1 N NaOH (1 mL). 5 mL EtOAc was added, and the r×n mixture wasstirred at rt for 12 h. The crude product was purified by prep. TLCeluting with 50% EtOAc/Hexanes to give the title compound as a yellowishsolid (44 mg). LC-MS (M−H₂O+H)⁺=290.05.

Preparation AN2-chloro-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one

Intermediate AN(1)

2,4-dichloro-6-(1-phenylvinyl)pyrimidin-5-yl)methanol

A mixture of 2,4,6-trichloropyrimidin-5-yl)methanol (1.1 g),1-phenylvinylboronic acid (0.8 g), Tetrakis (0.3 g), sodium carbonate(1.64 g) in toluene (14 mL) and water (3 mL) was heated at 100° C. for12 h. Water was added followed by ethyl acetate, the aqueous layer wasextracted with ethyl acetate (×3), and the combined organic layers weredried over anhydrous sodium sulfate and then filtered. The filtrate wasconcentrated, and the residue was purified Biotage eluting with 10-40%EtOAc/Hexanes to give the title compound as a white solid (325 mg).LC-MS (M+H)⁺=281.02. ¹H NMR (500 MHz, chloroform-d) δ ppm 7.5 (5H, m),6.01 (1H, s), 5.67 (1H, s), 4.62 (2H, s).

Intermediate AN(2)

2,4-dichloro-6-(1-phenylvinyl)pyrimidine-5-carbaldehyde

To a solution of 2,4-dichloro-6-(1-phenylvinyl)pyrimidin-5-yl)methanol(327 mg) in CH₂Cl₂ was added PCC (600 mg) and 4A MS (600 mg), and ther×n mixture was stirred at rt for 30 min. The solution turned to darkbrown from orange a few min after addition of PCC. The reaction mixturewas filtered through a pad of silica gel eluting with CH₂Cl₂ to give thetitle compound as a s a brownish solid (209 mg) and used directly forthe next step.

Intermediate AN(3)

1-(2,4-dichloro-6-(1-phenylvinyl)pyrimidin-5-yl)prop-2-en-1-ol

To a solution of 2,4-dichloro-6-(1-phenylvinyl)pyrimidine-5-carbaldehyde(200 mg) in THF (3.6 mL) at −78 C. was added vinylmagnesium bromide(0.79 mL, 1M solution in THF) dropwise, and the reaction mixture wasstirred at −78° C. for 20 min. Saturated NH₄Cl was added followed byethyl acetate, the aqueous layer was extracted with ethyl acetate (×3),and the combined organic layers were dried over anhydrous sodium sulfateand then filtered. The filtrate was concentrated in vacuo to give thetitle compound (156 mg) as a colorless oil. The crude product was useddirectly for the next step.

Preparation AN2-chloro-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one

To a solution of1-(2,4-dichloro-6-(1-phenylvinyl)pyrimidin-5-yl)prop-2-en-1-ol (20 mg)in CH₂Cl₂ (6.5 mL) was added Grubbs II catalyst (6 mg), and the reactionmixture was heated under reflux for 30 min The solvent was removed, andthe residue was dissolved in EtOAc (4 mL), and 10% Pd/C (5 mg) wasadded. The reaction mixture was stirred under a hydrogen balloon for 35min. Hydrogen balloon was removed, and then Hunig's base (23 μL) wasadded followed by methylamine (36 μL, 2 M solution in methanol). Thereaction mixture was stirred at room temperature for 10 min, and thesolvents were removed. The residue was purified by preparative TLCeluting with 35% EtOAc/Hexanes to give the title compound as a yellowsolid (6.6 mg, 37% yield). ¹H NMR (500 MHz, chloroform-d) δ ppm 7.1-7.4(5H, m), 4.45 (1H, dd, J=3.0, 8.0 Hz), 3.24 (1H, dd, J=8.0, 19.5 Hz),3.20 (3H, s), 3.19 (3H, s), 2.71 (1H, dd, J=3.0, 19.5 Hz). ¹³C NMR (125MHz, chloroform-d) δ 203.12, 186.69, 166.52, 159.93, 139.88 129.16 (2C),127.73 (2C), 127.59, 110.98, 46.50, 45.48, and 27.53. HRMS calcd. forC₁₄H₁₃ClN₃O (M+H) 274.0742; found: 274.0741.

Preparation AO 3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline

A DMF solution of diethyl 1-methyl-1H-pyrazol-4-ylboronate,4-bromo-3-methoxy nitrobenzene together with Pd(dppf) and K2CO3 wereheated at reflux overnight. The product obtained was reduced with Fe inMeOH/ammonium chloride to provide the title compound. LC-MS(M+H)⁺=204.2. ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.84 (1H, s), 7.66 (1H,s), 7.19 (1H, J=8.2 Hz, d), 6.29 (1H, s), 6.18 (1H, J=2.0, 8.2 Hz, dd),5.31 (2H, br s), 3.80 (3H, s), 3.75 (3H, s).

EXAMPLES Example 1N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The method of Example 74 was used to combine Preparation Ga and3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation D) toaffordN2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 1). LC-MS (M+H)⁺=428.2. ¹H NMR (500 MHz, MeOD) δ ppm 8.95 (1H,br. s.), 7.72 (1H, d, J=2.14 Hz), 7.65 (1H, d, J=8.55 Hz), 7.37-7.42(2H, m), 7.30-7.34 (1H, m), 7.26 (2H, d, J=7.02 Hz), 7.22 (1H, dd,J=8.85, 2.14 Hz), 4.42-4.48 (1H, m), 3.93 (3H, s), 3.16 (3H, s),2.88-2.96 (1H, m), 2.72-2.83 (2H, m), 2.46 (3H, s), 2.12-2.21 (1H, m).

Example 2N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The method of Example 74 was used to combine Preparation Ga and3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation B) toaffordN2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 2). LC-MS (M+H)⁺=416.2. ¹H NMR (500 MHz, MeOD) δ ppm 8.77 (1H,br. s.), 7.95 (1H, dd, J=13.43, 2.14 Hz), 7.77 (1H, t, J=8.70 Hz), 7.48(1H, dd, J=8.85, 1.53 Hz), 7.40 (2H, t, J=7.48 Hz), 7.33 (1H, t, J=7.48Hz), 7.28 (2H, d, J=7.02 Hz), 4.49 (1H, dd, J=7.63, 4.58 Hz), 3.18 (3H,s), 2.88-2.98 (1H, m), 2.77-2.86 (2H, m), 2.46 (3H, s), 2.14-2.24 (1H,m).

Example 3N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The method of Example 74 was used to combine Preparation Ga and3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation C) toaffordN2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 3). LC-MS (M+H)⁺=416.2. ¹H NMR (500 MHz, MeOD) δ ppm 8.11 (1H,s), 7.99 (1H, dd, J=12.51, 1.83 Hz), 7.51-7.60 (2 H, m), 7.41 (2H, t,J=7.48 Hz), 7.31-7.36 (1H, m), 7.28 (2H, d, J=7.02 Hz), 4.47-4.54 (1H,m), 2.90-3.00 (1H, m), 2.76-2.87 (2H, m), 2.42 (3H, s), 2.15-2.26 (1H,m).

Example 3A

N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

Example 3 was separated by multiple chiral prep HPLC injections (OJ-H30×250 mm, 10 μM, 30% EtOH/Heptane/0.1% DEA) to giveN²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(first to elute, enantiomer A) as a slightly yellow, opaque glass. LC-MS(M+H)⁺=416.2. ¹H NMR (500 MHz, MeOD) δ ppm 8.15 (1H, dd, J=13.73, 2.14Hz), 8.03 (1H, s), 7.36-7.42 (1H, m), 7.28-7.36 (3H, m), 7.16-7.26 (3H,m), 4.21 (1H, t, J=7.78 Hz), 3.07-3.13 (3H, m), 2.78-2.88 (1H, m),2.59-2.76 (2H, m), 2.35-2.41 (3 H, m), 1.99-2.13 (1H, m).

Example 3BN²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

Enantiomer B ofN2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diaminewas prepared as per Example 3A except that it was the second to eluteoff of the chiral HPLC column as a slightly yellow, opaque glass. LC-MS(M+H)⁺=416.2. ¹H NMR (500 MHz, MeOD) δ ppm 8.17 (1H, dd, J=13.89, 2.29Hz), 8.02 (1H, s), 7.28-7.46 (4H, m), 7.16-7.27 (3 H, m), 4.19 (1H, t,J=7.78 Hz), 3.05-3.16 (3H, m), 2.78-2.89 (1H, m), 2.57-2.78 (2 H, m),2.33-2.48 (3H, m), 1.99-2.17 (1H, m).

Example 4N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-N,N-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(200 mg, 0.731 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (163 mg, 0.731 mmol) inTHF (1 mL) and acetic acid (1.000 mL). The reaction mixture was stirredovernight at 75° C. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (180.7 mg, 0.308 mmol, 42.2% yield). LC-MS (M+H)⁺=461.2. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.12 (1H, s), 7.98-8.17 (2H, m), 7.09-7.56 (6H,m), 7.01-7.09 (1H, m), 4.31-4.52 (2H, m), 3.97 (1H, s), 3.81-3.89 (2H,m), 3.45-3.55 (2H, m), 3.32-3.43 (3H, m), 3.16-3.29 (2H, m), 2.81-3.03(1H, m), 2.56-2.75 (2H, m), 2.07-2.32 (2H, m).

Example 4A & 4B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 4) was purified using chiral SFC to afford peak A (Example 4A)and peak B (Example 4B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM),35% methanol (0.1% diethylamine) in CO₂, 35° C., flow rate 2.0 mL/minfor 22 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution inmethanol (multiple stacked injections), t_(R) (peak A)=5.1 min, t_(R)(peak B) 18.1 min. The absolute stereochemistry of individualenantiomers (Examples 4A and 4B) was not determined LC-MS and ¹H NMRanalytical data for the separated enantiomers was identical to theracemate (Example 4).

Example 5N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-N-ethyl-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(160 mg, 0.556 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (124 mg, 0.556 mmol) inTHF (1.5 mL) and acetic acid (1.5 mL). The reaction mixture was stirredovernight at 80° C. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(85.3 mg, 0.171 mmol, 30.7% yield). LC-MS (M+H)⁺=475.2. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.49-7.61 (1H, m), 7.38 (1H, br. s.), 7.23-7.34 (6H, m),7.13 (1H, d, J=8.5 Hz), 7.05 (1H, s), 4.35 (1H, dd, J=9.3, 4.1 Hz),3.69-3.82 (4H, m), 3.47 (2H, br. s.), 3.27-3.38 (4H, m), 3.11-3.23 (1H,m), 2.56-2.72 (1H, m), 2.24 (1H, ddd, J=9.0, 4.4, 4.3 Hz), 1.31 (3H, t,J=7.2 Hz).

Example 5A & 5B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 5) was purified using chiral SFC to afford peak A (Example 5A)and peak B (Example 5B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM),35% methanol (0.1% diethylamine) in CO₂, 35° C., flow rate 2.0 mL/minfor 22 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution inmethanol (multiple stacked injections), t_(R) (peak A)=4.5 min, t_(R)(peak B) 16.7 min. The absolute stereochemistry of individualenantiomers (Examples 5A and 5B) was not determined LC-MS and ¹H NMRanalytical data for the separated enantiomers was identical to theracemate (Example 5).

Example 64-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

4-(Azetidin-1-yl)-2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine(162 mg, 0.567 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (127 mg, 0.567 mmol) inacetic acid (1.000 mL) and THF (1 mL). The reaction mixture was heatedat 80° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to afford4-(azetidin-1-yl)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA salt (39.2 mg, 0.066 mmol, 11.66% yield). LC-MS (M+H)⁺=473.2. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.44 (1H, s), 7.94 (1H, d, J=1.5 Hz), 7.52 (1H,d, J=2.1 Hz), 7.27-7.44 (4H, m), 6.96-7.23 (3H, m), 4.64 (3H, br s),4.38 (2H, d, J=7.6 Hz), 3.83 (2H, s), 3.29-3.52 (1H, m), 3.11 (1H, d,J=7.9 Hz), 2.98 (1H, s), 2.62-2.76 (1H, m), 2.57 (2H, s), 2.14-2.38 (2H,m).

Example 6A & 6B(S)-4-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amineand(R)-4-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

A racemic mixture of4-(azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 6) was purified using chiral SFC to afford peak A (Example 6A)and peak B (Example 6B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM),35% methanol (0.1% diethylamine) in CO₂, 35° C., flow rate 2.0 mL/minfor 30 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in50:50 methanol/chloroform (multiple stacked injections), t_(R) (peakA)=5.9 min, t_(R) (peak B) 24.6 min. The absolute stereochemistry ofindividual enantiomers (Examples 6A and 6B) was not determined LC-MS and¹H NMR analytical data for the separated enantiomers was identical tothe racemate (Example 6).

Example 7N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A solution of2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(833 mg, 3.21 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(717.9 mg, 3.21 μmol) in THF (5.6 mL) and acetic acid (5.6 mL) washeated at 85° C. in a 350 mL high-pressure vessel overnight. The solventwas removed in vacuum and the residue was dissolved in dichloromethaneand washed with saturated aqueous sodium bicarbonate solution. Theorganic phase was separated and the aqueous phase was extracted withdichloromethane. The combined organic extracts were dried over anhydrousmagnesium sulfate and filtered. The solvent was removed in vacuum andthe residue was purified by column chromatography on silica gel to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,which was contaminated with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline. The material wastriturated with methanol, cooled in the freezer and filtered. Theresidue was washed with freezing cold methanol and dried to give pureN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(673.5 mg, 47%) as light brown solid. LC-MS (M+H)⁺=446.9. ¹H NMR (500MHz, CDCl₃) δ ppm 7.99 (1H, d, J=1.8 Hz), 7.48 (1H, s), 7.27-7.33 (2H,m), 7.16-7.24 (3H, m), 6.96-7.07 (3H, m), 6.71 (1H, dd, J=8.4, 1.7 Hz),4.50 (1H, br s), 4.20 (1H, s), 3.48 (3H, s), 3.11 (3H, d, J=4.9 Hz),2.59-2.79 (3H, m), 2.01-2.13 (1H, m).

Examples 7A and 7B(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(92 mg, 0.206 mmol from Example 7) was purified using chiralsupercritical fluid chromatography (SFC) to afford 28.4 mg of peak A(Example 7A) and 27.4 mg of peak B (Example 7B). SFC Method: ChiralpakOJ-H (30×250 mm, 5 μM), 40% methanol (0.1% diethylamine) in CO₂, 35° C.,flow rate 70 mL/min for 16 min, absorbance 268 nm, injection 1 mL of 15mg/mL solution in methanol (multiple stacked injections), t_(R) (peakA)=5.0 min, t_(R) (peak B) 12.3 min. The absolute stereochemistry ofindividual enantiomers (Examples 7A and 7B) was not determined. LC-MSand ¹H NMR analytical data for the separated enantiomers was identicalto the racemate (Example 7).

Example 8N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

To a mixture of2-chloro-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(175 mg, 0.612 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(151 mg, 0.674 mmol) in NMP (2 mL) was added Conc. H2SO4 (0.046 mL,0.857 mmol). The mixture was stirred at 97° C. for 20 hours. Aftercooled down to room temperature, 100 mL of EtOAc was added, washed withsaturated NaHCO3/water and water, dried over Na2SO4, and finallyremoved. The residue was purified via Biotage (12 g, hexanes-80% EtOAc)to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(200 mg, 0.423 mmol, 69.1% yield). LC-MS (M+H)⁺=473.10. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.81 (1H, d, J=1.8 Hz), 7.51 (1H, d, J=1.5 Hz), 7.44 (1H,s), 7.27-7.35 (2H, m), 7.19-7.25 (3H, m), 6.99-7.06 (2H, m), 6.95 (1H,d, J=8.2 Hz), 4.89 (1H, br. s.), 4.20 (1H, t, J=8.2 Hz), 3.45 (3H, s),2.92 (1H, td, J=6.7, 3.1 Hz), 2.76-2.86 (1H, m), 2.59-2.75 (2H, m),2.07-2.14 (1H, m), 0.85-0.91 (2H, m), 0.63-0.70 (2H, m).

Example 9N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

To a mixture of2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(165 mg, 0.55 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(135 mg, 0.605 mmol) in NMP (2 mL) was added Conc. H2SO4 (0.041 mL,0.771 mmol). The mixture was stirred at 97° C. for 20 hours. Aftercooled down to room temperature, 100 mL of EtOAc was added, washed withsaturated NaHCO3/water and water, dried over Na2SO4, and finallyremoved. The residue was purified via Biotage (12 g, hexanes-80% EtOAc)to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(202 mg, 0.394 mmol, 71.6% yield). LC-MS (M+H)⁺=487.14. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.92 (1H, d, J=1.8 Hz), 7.51 (1H, d, J=1.2 Hz), 7.28-7.33(2 H, m), 7.18-7.24 (3H, m), 7.13 (1H, s), 7.03 (1H, d, J=8.5 Hz), 7.01(1H, d, J=1.2 Hz), 6.74 (1H, dd, J=8.5, 2.1 Hz), 4.64-4.80 (2H, m),4.17-4.23 (1H, m), 3.49 (3H, s), 2.72-2.81 (1H, m), 2.61-2.71 (2H, m),2.43-2.53 (2H, m), 2.09 (1H, td, J=8.0, 2.3 Hz), 1.92-2.04 (2H, m),1.70-1.88 (2H, m).

Example 10N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

To a solution of2-chloro-N-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(154 mg, 0.535 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(114 mg, 0.508 mmol) in DMF (2.5 mL) was added Conc. H2SO4 (0.040 mL,0.749 mmol). The mixture was stirred at 94° C. for 20 hrs. After cooleddown to room temperature, 100 mL of EtOAc was added, washed withsaturated NaHCO3/H2O, dried over Na2SO4, and removed. The residue waspurified via Biotage (12 g, hexanes-100% EtOAC) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(120 mg, 0.253 mmol, 47.2% yield). LC-MS (M+H)⁺=475.2. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.92 (1H, d, J=2.1 Hz), 7.51 (1H, d, J=1.5 Hz), 7.31 (2H,d, J=7.3 Hz), 7.22-7.25 (2H, m), 7.22 (1H, s), 7.08 (1H, s), 7.04 (1H,d, J=8.5 Hz), 7.01 (1H, d, J=1.5 Hz), 6.74 (1H, dd, J=8.4, 2.3 Hz),4.38-4.46 (1H, m), 4.33 (1H, d, J=7.9 Hz), 4.18-4.24 (1H, m), 3.49 (3H,s), 2.72-2.80 (1H, m), 2.61-2.71 (2H, m), 2.07-2.14 (1H, m), 1.33 (6H,t, J=6.6 Hz).

Example 11N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A solution of2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(307.5 mg, 1.107 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (248 mg, 1.107 mmol) inTHF (3 mL) and acetic acid (3.00 mL) was heated at 80° C. overnight. Thesolvent was removed in vacuum and the residue was triturated withmethanol, cooled in the freezer and filtered. The precipitate wasthoroughly washed with methanol and dried to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(207.9 mg, 0.447 mmol, 40.4% yield) as off-white solid. LC-MS(M+H)⁺=465.0. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.18 (1H, s), 8.15 (1H, d,J=1.8 Hz), 7.73 (1H, d, J=1.5 Hz), 7.41 (1H, d, J=1.5 Hz), 7.18-7.26(2H, m), 7.07-7.18 (2H, m), 6.88-7.00 (1H, m), 4.12-4.20 (1H, m),4.04-4.12 (1H, br s), 3.60 (3H, s), 3.17 (1H, s), 2.96 (3H, d, J=4.6Hz), 2.71-2.81 (1H, m), 2.52-2.66 (2H, m), 1.83-1.96 (1H, m).

Examples 11A and 11B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(150 mg, 0.206 mmol from Example 11) was purified using chiralsupercritical fluid chromatography (SFC) to afford 74.6 mg of peak A(Example 11A) and 71.7 mg of peak B (Example 11B). SFC Method: ChiralpakOJ-H (30×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO₂, 35° C.,flow rate 70 mL/min for 12 min, absorbance 268 nm, injection 0.75 mL of15 mg/mL solution in methanol (multiple stacked injections), t_(R) (peakA)=4.0 min, t_(R) (peak B) 8.6 min. The absolute stereochemistry ofindividual enantiomers (Examples 11A and 11B) was not determined LC-MSand ¹H NMR analytical data for the separated enantiomers was identicalto the racemate (Example 11).

Example 12N²-(3-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

To a solution of2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(105.0 mg, 0.378 mmol) and3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (72.7 mg, 0.378 mmol)in THF (2 mL) was added 60% suspension of sodium hydride in mineral oil(30.2 mg, 0.756 mmol). The reaction mixture was stirred at 80° C. for 40minutes. The reaction mixture was further stirred at 80° C. for 4 h. Thereaction mixture was quenched with an aqueous solution of ammoniumchloride and extracted with dichloromethane. The combined organicextracts were dried over anhydrous magnesium sulfate and filtered. Thesolvent was removed in vacuum and the residue was purified by a reversedphase preparative HPLC system to giveN²-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,2 TFA (45.6 mg, 0.069 mmol, 18.25% yield) as brown oil. LC-MS(M+H)⁺=434.0. ¹H NMR (500 MHz, methanol-d4) δ ppm 8.86 (1H, s), 7.88(1H, t, J=8.4 Hz), 7.21-7.31 (3H, m), 7.19 (1H, d, J=8.9 Hz), 7.07 (2H,t, J=8.7 Hz), 4.27 (1H, t, J=8.5 Hz), 3.73 (3H, s), 3.33 (3H, s), 2.52(1H, dd, J=8.2, 4.0 Hz), 2.49 (3H, s), 2.38 (1H, d, J=7.6 Hz), 2.30 (1H,d, J=3.7 Hz), 1.95-2.07 (1H, m).

Example 13N²-(2-Fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

To a solution of2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(105.0 mg, 0.378 mmol) and2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (84 mg,0.378 mmol) in THF (2 mL) was added 60% suspension of sodium hydride inmineral oil (9.07 mg, 0.378 mmol). The reaction mixture was stirred at80° C. for 40 minutes. The reaction mixture was further stirred at 80°C. for 4 h. The reaction mixture was quenched with an aqueous solutionof ammonium chloride and extracted with dichloromethane. The combinedorganic extracts were dried over anhydrous magnesium sulfate andfiltered. The solvent was removed in vacuum and the residue was purifiedby a reversed phase preparative HPLC system to giveN²-(2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,2 TFA (20.2 mg, 0.027 mmol, 7.19% yield) as brown oil. LC-MS(M+H)⁺=464.0. ¹H NMR (500 MHz, methanol-d4) δ ppm 9.06 (1H, s), 7.74(1H, d, J=10.4 Hz), 7.19-7.28 (3H, m), 7.07 (2H, t, J=8.5 Hz), 4.24 (1H,s), 4.00 (3H, s), 3.76 (3H, s), 2.48 (3H, s), 2.40-2.54 (1H, m),2.26-2.38 (2H, m), 1.89-2.02 (1H, m).

Example 14N²-(6-(4-Chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

To a solution of2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(165.3 mg, 0.595 mmol) and6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (134 mg, 0.595mmol) in THF (3.5 mL) was added 60% suspension of sodium hydride inmineral oil (28.6 mg, 1.190 mmol). The reaction mixture was heated at80° C. in a capped vial for 6 h. The reaction was carefully quenchedwith aqueous ammonium chloride solution and the product was extractedwith dichloromethane. The combined organic extracts were dried overanhydrous magnesium sulfate and filtered. The solvent was removed invacuum and the residue was purified by a reversed-phase preparative HPLCmethod to provideN²-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,2 TFA (26.2 mg, 0.029 mmol, 4.88% yield) as brown oil. LC-MS(M+H)⁺=466.0. ¹H NMR (500 MHz, methanol-d4) δ ppm 8.43 (1H, s), 7.96(1H, s), 7.87 (1H, s), 7.55 (1H, br. s.), 7.19-7.32 (2H, m), 7.07 (2H,t, J=8.7 Hz), 4.20-4.29 (1H, m), 4.06 (3H, s), 3.75 (3H, s), 2.42-2.55(1H, m), 2.21-2.39 (2H, m), 1.90-2.05 (1H, m).

Example 15N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

A solution of2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(42.6 mg, 0.125 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(28.0 mg, 0.125 mmol) in THF (1 mL) and acetic acid (1.000 mL) washeated at 80° C. overnight. The heating was continued at 120° C.overnight. Upon cooling, the reaction mixture was purified by columnchromatography on silica gel to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (11.8 mg, 0.018 mmol, 14.54% yield) as brown oil. LC-MS(M+H)⁺=527.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 11.75 (1H, s), 8.02 (1H, s),7.40 (1H, dd, J=8.5, 2.1 Hz), 7.32 (1H, d, J=2.1 Hz), 7.16-7.23 (3H, m),7.12 (1H, s), 7.02 (2H, t, J=8.7 Hz), 4.42 (1H, dd, J=9.5, 4.9 Hz), 4.80(4H, s), 3.85 (3H, s), 3.11 (1H, s), 2.98 (1H, s), 2.67-2.79 (1H, m),2.26 (1H, d).

Example 164-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

To a solution of2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation Ha) (170 mg, 0.500 mmol) in THF (1498 μL) was added3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation C) (125mg, 0.650 mmol) and Acetic Acid (1498 μL). The resulting mixture washeated to 100° C. and stirred overnight. The reaction mixture was thenconcentrated in vacuo and purified by prep HPLC (C18, 30×150 mm,MeOH/H₂O/TFA) to give4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (racemate) (101.49 mg, 33.27% yield) as a beige solid. LC-MS(M+H)⁺=496.1. ¹H NMR (500 MHz, MeOD) δ ppm 8.06-8.11 (1H, m), 7.86 (1H,dd, J=12.51, 2.14 Hz), 7.47-7.57 (2H, m), 7.28-7.35 (2H, m), 7.11-7.19(2H, m), 4.93 (4H, t, J=11.90 Hz), 4.47 (1H, t, J=7.93 Hz), 3.11-3.18(1H, m), 2.99-3.08 (1H, m), 2.71-2.81 (1H, m, J=13.31, 8.91, 8.91, 4.27Hz), 2.42 (3H, s), 2.08-2.19 (1H, m, J=13.24, 9.04, 6.71, 6.71 Hz).

Example 16A4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 16) was separated by multiple injections on chiral SFC(Chiracel OJ-H 30×250 mm, 5 μM, 30% MeOH (0.1% DEA)/CO₂ to give4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, enantiomer A) as an off-white solid. LC-MS(M+H)⁺=496.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.87-8.08 (2H, m), 7.35-7.44(1H, m), 7.31 (1H, t, J=8.70 Hz), 7.24 (2H, dd, J=8.55, 5.49 Hz), 7.04(2H, t, J=8.70 Hz), 4.64 (4H, t, J=12.05 Hz), 4.19 (1H, t, J=8.24 Hz),2.98-3.08 (1H, m), 2.86-2.98 (1H, m), 2.55-2.68 (1H, m, J=12.86, 8.60,8.60, 4.12 Hz), 2.37 (3H, s), 1.97-2.12 (1H, m). The absolutestereochemistry of Example 16A was not determined.

Example 16B4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 16) was separated by multiple injections on chiral SFC(Chiracel OJ-H 30×250 mm, 5 μM, 30% MeOH (0.1% DEA)/CO₂ to give4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(second to elute, enantiomer B) as an off-white solid. LC-MS(M+H)⁺=496.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.96-8.09 (2H, m), 7.39 (1H,dd, J=9.00, 1.98 Hz), 7.32 (1H, t, J=8.55 Hz), 7.20-7.28 (2H, m),6.99-7.11 (2 H, m), 4.65 (4H, t, J=12.21 Hz), 4.20 (1H, t, J=8.24 Hz),2.99-3.09 (1H, m), 2.88-2.99 (1H, m), 2.56-2.71 (1H, m), 2.31-2.46 (3H,m), 1.98-2.15 (1H, m). The absolute stereochemistry of Example 16B wasnot determined.

Example 17N-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

To a solution of2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation Ha) (170 mg, 0.500 mmol) and4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (Preparation F) (146mg, 0.650 mmol) in THF (1498 μL) was added Acetic Acid (1498 μL). Theresulting mixture was heated to 100° C. and stirred overnight. Thereaction mixture was then concentrated in vacuo. MeOH was added to theresidue which resulted in a suspension. This was filtered to give asolid which was taken up in hot MeOH and filtered. The filtrate was thenconcentrated in vacuo to giveN-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(racemate) (130 mg, 49.22% yield) as a yellow solid. LC-MS (M+H)⁺=528.1.¹H NMR (500 MHz, MeOD) δ ppm 8.81 (1H, s), 7.65 (1H, d, J=8.55 Hz), 7.59(1H, s), 7.29-7.36 (2H, m), 7.11-7.21 (3H, m), 4.87-4.88 (4H, m), 4.47(1H, s), 3.91 (3H, s), 3.11-3.19 (1H, m), 2.99-3.08 (1H, m), 2.77 (1H,dddd, J=13.47, 8.96, 4.43, 4.27 Hz), 2.13 (1H, dq, J=8.89, 6.70 Hz).

Example 17AN-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 17) was separated by multiple injections on chiral SFC(Chiracel AD-H 30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂ to give4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, enantiomer A) as a yellow film. LC-MS (M+H)⁺=528.1. ¹HNMR (500 MHz, DMSO-d6) δ ppm 8.82 (1H, d, J=1.53 Hz), 8.06 (1H, s), 7.35(1H, d, J=8.85 Hz), 7.21-7.31 (2H, m), 7.07-7.21 (3H, m), 4.70 (4H, t,J=12.36 Hz), 4.20 (1H, t, J=8.24 Hz), 3.63 (3H, br. s.), 3.01 (1H, br.s.), 2.80-2.95 (1H, m), 2.53-2.63 (1H, m), 1.93 (1H, d, J=8.24 Hz). Theabsolute stereochemistry of Example 17A was not determined.

Example 17BN-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 17) was separated by multiple injections on chiral SFC(Chiracel AD-H 30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂ to give4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(second to elute, enantiomer B) as a yellow film. LC-MS (M-FH)⁺=528.1.¹H NMR (500 MHz, DMSO-d6) δ ppm 8.76-8.92 (1H, m), 8.06 (1H, br. s.),7.30-7.45 (1H, m), 7.25 (2H, d, J=5.49 Hz), 7.05-7.19 (3H, m), 4.57-4.80(4H, m), 4.20 (1H, br. s.), 3.63 (3H, br. s.), 3.00 (1H, br. s.),2.82-2.94 (1H, m), 2.53-2.61 (1H, m), 1.91 (1H, br. s.). The absolutestereochemistry of Example 17B was not determined.

Example 184-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

(1S,4S)-5-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane(Preparation Hb) (148 mg, 0.428 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (124 mg,0.556 mmol) were combined and purified as per Example 16 to give4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (diastereomer mixture) (106 mg, 0.164 mmol, 38.3% yield) as a brownsolid. LC-MS (M+H)⁺=533.1. ¹H NMR (500 MHz, DMSO-d6) δ ppm 7.81 (1H, s),7.67 (1H, br. s.), 7.49 (1H, s), 7.32 (3H, d, J=7.93 Hz), 7.19 (2H, t,J=8.70 Hz), 7.14 (1H, d, J=2.14 Hz), 5.17 (1H, br. s.), 4.74 (1H, s),4.34 (1H, br. s.), 3.58-3.95 (7H, m), 2.89-3.39 (2H, m), 2.55 (1H, s),1.97 (3H, br. s.).

Example 18A4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 18) was separated by multiple chiral SFC injections (OD-H30×250 mm, 5 μM, 30% MeOH (0.1% DEA)/CO₂) to give4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, enantiomer A) as a beige residue. LC-MS (M+H)⁺=532.9.¹H NMR (500 MHz, MeOD) δ ppm 7.82 (1H, br. s.), 7.67 (1H, s), 7.18-7.30(3H, m), 7.11-7.18 (1H, m), 6.96-7.09 (3H, m), 5.14 (1H, br. s.), 4.72(1H, br. s.), 4.18 (1H, t, J=8.55 Hz), 3.94-4.01 (1H, m), 3.92 (1H, d,J=6.41 Hz), 3.78-3.86 (1H, m), 3.69-3.78 (1H, m), 3.57 (3H, s),3.01-3.15 (2H, m), 2.51-2.69 (1H, m), 1.84-2.11 (3H, m). The absolutestereochemistry of Example 18A was not determined.

Example 18B4-((1S,4S)-2-oxa-5-azabicyclo[2.2.4]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 18) was separated by multiple chiral SFC injections (OD-H30×250 mm, 5 μM, 30% MeOH (0.1% DEA)/CO₂) to give4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(second to elute, enantiomer B) as a beige residue. LC-MS (M+H)⁺=532.9.¹H NMR (500 MHz, MeOD) δ ppm 7.20-7.31 (3H, m), 7.17 (1H, d, J=8.55 Hz),7.05 (3H, t, J=8.09 Hz), 5.17 (1H, br. s.), 4.72 (1H, s), 4.14 (1H, t,J=8.09 Hz), 3.94-4.02 (1H, m), 3.89-3.94 (1H, m), 3.70-3.85 (2H, m),3.50-3.68 (3H, m), 3.20-3.31 (1H, m), 2.96 (1H, ddd, J=14.65, 7.78, 7.48Hz), 2.48-2.66 (1H, m, J=13.08, 8.72, 8.72, 4.27 Hz), 1.89-2.11 (3H, m).The absolute stereochemistry of Example 18B was not determined.

Example 19N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

2-chloro-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidinen(Preparation Hc1) (159 mg, 0.479 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (139 mg,0.623 mmol) were combined and purified as per Example 16 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (racemate, diastereomer 1) (84.37 mg, 0.133 mmol, 27.8% yield) as abrown solid. LC-MS (M+H)⁺=519.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.80 (1H,s), 7.41 (1H, d, J=8.55 Hz), 7.30-7.37 (4H, m), 7.21-7.32 (1H, m), 7.17(2H, t, J=8.55 Hz), 4.68 (1H, br. s.), 4.44 (1H, br. s.), 3.94-4.23 (2H,m), 3.88 (3H, s), 3.37 (3H, s), 3.18 (1H, s), 2.72 (1H, br. s.), 2.11(4H, br. s.), 1.83 (1H, br. s.). The relative stereochemistry of Example19 was not determined.

Example 19AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 19) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, enantiomer A, diastereomer 1) as a brown wax. LC-MS(M+H)⁺=519.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.76 (1H, s), 7.66 (1H, d,J=1.53 Hz), 7.16-7.27 (3H, m), 7.07-7.16 (2H, m), 7.02 (2H, t, J=8.85Hz), 4.54 (1H, t, J=5.65 Hz), 4.07 (1H, t, J=8.24 Hz), 3.91 (1H, dt,J=10.45, 4.08 Hz), 3.68-3.79 (1H, m), 3.54-3.68 (3H, m), 3.15-3.28 (1H,m), 2.96-3.13 (1H, m), 2.45-2.58 (1H, m), 2.02-2.18 (2H, m), 1.95-2.02(1H, m), 1.85-1.95 (1H, m), 1.67-1.81 (1H, m), 1.27 (3H, d, J=6.10 Hz).The absolute stereochemistry of Example 19A was not determined.

Example 19BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 19) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(second to elute, enantiomer B, diastereomer 1) as a brown wax. LC-MS(M+H)⁺=519.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.76 (1H, d, J=1.53 Hz), 7.65(1H, d, J=1.22 Hz), 7.15-7.23 (3H, m), 7.06-7.14 (2H, m), 6.96-7.05 (2H,m), 4.48-4.57 (1H, m), 4.05 (1H, t, J=8.39 Hz), 3.85-3.94 (1H, m),3.66-3.76 (1H, m), 3.60 (3H, s), 3.16-3.26 (1H, m), 2.95-3.08 (1H, m),2.44-2.55 (1H, m, J=12.78, 8.56, 8.56, 3.97 Hz), 2.01-2.14 (2H, m),1.94-2.01 (1H, m), 1.85-1.94 (1H, m), 1.68-1.77 (1H, m), 1.26 (3H, d,J=6.10 Hz). The absolute stereochemistry of Example 19B was notdetermined.

Example 20N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

2-chloro-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidinen(Preparation Hc2) (179 mg, 0.539 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (157 mg,0.701 mmol) were combined and purified as per Example 16 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (racemate, diastereomer 2) (99.55 mg, 0.157 mmol, 29.2% yield) as abrown solid. LC-MS (M+H)⁺=519.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.80 (1H,d, J=1.53 Hz), 7.41-7.60 (1H, m), 7.40 (1H, s), 7.30-7.37 (3 H, m),7.21-7.29 (1H, m), 7.16 (2H, t, J=8.70 Hz), 4.68 (1H, br. s.), 4.45 (1H,d, J=7.93 Hz), 4.17 (1H, br. s.), 4.00 (1H, br. s.), 3.88 (3H, s),3.34-3.48 (2H, m), 3.17-3.30 (1H, m), 2.73 (1H, br. s.), 2.11 (4H, br.s.), 1.81 (1H, br. s.), 1.35 (3H, d, J=6.41 Hz). The relativestereochemistry of Example 20 was not determined.

Example 20AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 20) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, enantiomer A, diastereomer 2) as a brown wax. LC-MS(M+H)⁺=519.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.75 (1H, d, J=1.83 Hz), 7.65(1H, d, J=1.53 Hz), 7.14-7.22 (3H, m), 7.05-7.14 (2H, m), 6.96-7.05 (2H,m), 4.55 (1H, td, J=6.41, 2.44 Hz), 4.10 (1H, t, J=8.39 Hz), 3.86-3.95(1H, m), 3.73 (1H, dt, J=10.15, 7.74 Hz), 3.59 (3H, s), 3.16-3.25 (1H,m), 3.06-3.16 (1H, m), 2.52 (1H, dddd, J=12.70, 8.70, 8.51, 3.97 Hz),2.02-2.16 (2H, m), 1.82-2.02 (2H, m), 1.65-1.78 (1H, m), 1.27 (3H, d,J=6.10 Hz). The absolute stereochemistry of Example 20A was notdetermined.

Example 20BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 20) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(second to elute, enantiomer B, diastereomer 2) as a brown wax. LC-MS(M+H)⁺=519.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.75 (1H, s), 7.65 (1H, d,J=1.53 Hz), 7.14-7.21 (3H, m), 7.05-7.14 (2H, m), 6.96-7.04 (2H, m),4.49-4.58 (1H, m), 4.10 (1H, t, J=8.55 Hz), 3.84-3.93 (1H, m), 3.69-3.78(1H, m), 3.55-3.61 (3H, m), 3.15-3.24 (1H, m), 3.05-3.15 (1H, m), 2.52(1H, dddd, J=12.67, 8.62, 8.47, 4.12 Hz), 2.02-2.17 (2H, m), 1.83-2.02(2H, m), 1.65-1.77 (1H, m), 1.23-1.32 (3H, m). The absolutestereochemistry of Example 20B was not determined.

Example 21N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

(2S,6R)-4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,6-dimethylmorpholine(Preparation Hd) (223 mg, 0.616 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (179 mg,0.801 mmol) were combined and purified as per Example 16 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (144 mg, 0.217 mmol, 35.2% yield) as a brown solid. LC-MS(M+H)⁺=549.0. ¹H NMR (500 MHz, MeOD) δ ppm 7.81 (1H, d, J=1.53 Hz), 7.41(1H, d, J=8.55 Hz), 7.28-7.38 (4H, m), 7.09-7.20 (3H, m), 4.62 (2 H, br.s.), 4.45 (1H, t, J=7.93 Hz), 3.83-3.89 (3H, m), 3.69-3.80 (2H, m),3.25-3.30 (1H, m), 3.13-3.23 (1H, m), 2.94 (2H, br. s.), 2.75 (1H, dddd,J=13.43, 8.93, 8.77, 4.88 Hz), 2.03-2.20 (1H, m), 1.25 (6H, d, J=6.10Hz).

Example 21AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 21) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 35% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, enantiomer A) as a brown wax. LC-MS (M+H)⁺=549.0. ¹HNMR (500 MHz, MeOD) δ ppm 7.81 (1H, d, J=2.14 Hz), 7.63 (1H, d, J=1.53Hz), 7.11-7.20 (3H, m), 7.08 (1H, d, J=8.55 Hz), 6.96-7.03 (2H, m), 6.92(1H, dd, J=8.55, 2.44 Hz), 4.27-4.41 (2H, m), 4.08 (1H, t, J=8.70 Hz),3.58-3.74 (2H, m), 3.49 (3H, s), 2.99-3.08 (1H, m), 2.87-2.99 (1H, m),2.55-2.72 (2H, m), 2.44-2.55 (1H, m), 1.83-1.96 (1H, m, J=12.70, 8.55,8.30, 8.30 Hz), 1.17-1.22 (6H, m). The absolute stereochemistry ofExample 21A was not determined.

Example 21BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 21) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 35% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(second to elute, enantiomer B) as a brown wax. LC-MS (M+H)⁺=549.0. ¹HNMR (500 MHz, MeOD) δ ppm 7.81 (1H, d, J=2.14 Hz), 7.63 (1H, d, J=1.53Hz), 7.11-7.19 (3H, m), 7.04-7.11 (1H, m), 6.95-7.03 (2H, m), 6.92 (1H,dd, J=8.39, 2.29 Hz), 4.27-4.42 (2H, m), 4.08 (1H, t, J=8.70 Hz),3.59-3.73 (2H, m), 3.49 (3H, s), 2.98-3.08 (1H, m), 2.88-2.98 (1H, m),2.55-2.70 (2H, m), 2.43-2.55 (1H, m), 1.79-1.97 (1H, m, J=12.70, 8.55,8.30, 8.30 Hz), 1.17-1.21 (6H, m). The absolute stereochemistry ofExample 21B was not determined.

Example 221-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol

1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol(Preparation He) (374 mg, 1.034 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (301 mg,1.344 mmol) were combined and purified as per Example 17 to give1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol(89 mg, 0.162 mmol, 15.68% yield) as a slightly yellow solid. LC-MS(M+H)⁺=549.3. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.82 (1H, s), 7.64 (1H,br. s.), 7.50 (1H, s), 7.27-7.43 (3H, m), 7.20 (3H, t, J=8.70 Hz), 7.06(1H, dd, J=8.39, 1.68 Hz), 4.36 (3H, br. s.), 3.73 (3H, br. s.),2.98-3.26 (3H, m), 2.59 (1H, br. s.), 1.88-2.06 (1H, m), 1.62 (4H, br.s.), 1.25 (2H, br. s.), 1.19 (3H, s).

Example 23N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

2-chloro-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation Hf1) (77 mg, 0.223 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (64.7 mg,0.289 mmol) were combined and purified as per Example 16 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (racemic, diastereomer 1) (53.31 mg, 0.082 mmol, 37.0% yield) as abrown solid. LC-MS (M+H)⁺=533.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.79 (1H,br. s.), 7.36-7.61 (2H, m), 7.34 (3H, br. s.), 7.17 (3H, br. s.), 4.44(2H, br. s.), 4.00 (2H, br. s.), 3.88 (3H, br. s.), 3.16-3.27 (1H, m),2.73 (2H, br. s.), 2.09 (5H, br. s.), 1.32 (2H, br. s.), 0.93 (3H, br.s.). The relative stereochemistry of Example 23 was not determined.

Example 23AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 23) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, enantiomer A) as a brown oil. LC-MS (M+H)⁺=533.3. ¹HNMR (500 MHz, MeOD) δ ppm 7.60-7.70 (2H, m), 7.17-7.26 (4H, m), 7.14(1H, d, J=8.55 Hz), 6.98-7.07 (2H, m), 4.26-4.36 (1H, m), 4.09 (1H, t,J=8.24 Hz), 3.83-3.92 (1H, m), 3.70-3.79 (1H, m), 3.63 (3H, s),3.15-3.25 (1H, m), 3.04 (1H, ddd, J=14.80, 7.63, 7.48 Hz), 2.48-2.60(1H, m, J=12.86, 8.60, 8.60, 4.12 Hz), 1.76-2.12 (6H, m), 1.40-1.53 (1H,m), 0.94-1.00 (3H, m). The absolute stereochemistry of Example 23A wasnot determined.

Example 23BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 23) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(second to elute, enantiomer B) as a brown oil. LC-MS (M+H)⁺=533.3. ¹HNMR (500 MHz, MeOD) δ ppm 7.60-7.70 (2H, m), 7.18-7.27 (4H, m), 7.14(1H, d, J=8.55 Hz), 7.03 (2H, t, J=8.70 Hz), 4.31 (1H, br. s.),4.04-4.13 (1H, m), 3.81-3.91 (1H, m), 3.70-3.80 (1H, m), 3.63 (3H, s),3.16-3.26 (1H, m), 3.05 (1H, ddd, J=14.65, 7.78, 7.48 Hz), 2.54 (1H,dddd, J=12.78, 8.70, 8.58, 4.12 Hz), 1.76-2.14 (6H, m), 1.41-1.54 (1H,m), 0.97 (3H, t, J=7.32 Hz). The absolute stereochemistry of Example 23Bwas not determined.

Example 24N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

2-chloro-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation Hf2) (80 mg, 0.231 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (67.3 mg,0.301 mmol) were combined and purified as per Example 16 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (racemic, diastereomer 2) (39.54 mg, 0.061 mmol, 26.4% yield) as abrown solid. LC-MS (M+H)⁺=533.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.78 (1H,s), 7.28-7.44 (5H, m), 7.17 (3H, t, J=8.09 Hz), 4.46 (2H, br. s.), 4.00(2H, br. s.), 3.88 (3H, s), 3.37 (1H, br. s.), 2.73 (2H, br. s.), 2.09(6H, d, J=4.27 Hz), 1.27-1.73 (1H, m), 0.87 (3H, br. s.). The relativestereochemistry of Example 24 was not determined.

Example 24AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 24) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, enantiomer A) as a brown oil. LC-MS (M+H)⁺=533.3. ¹HNMR (500 MHz, MeOD) δ ppm 7.58-7.71 (2H, m), 7.16-7.26 (4H, m),7.10-7.16 (1H, m), 6.97-7.08 (2H, m), 4.29-4.39 (1H, m), 4.14 (1H, t,J=8.39 Hz), 3.82-3.93 (1H, m), 3.72-3.82 (1H, m), 3.61 (3H, s),3.17-3.26 (1H, m), 3.12 (1H, ddd, J=14.80, 7.63, 7.48 Hz), 2.56 (1H,dddd, J=12.70, 8.70, 8.51, 3.97 Hz), 1.79-2.09 (6H, m), 1.40-1.56 (1H,m), 0.97 (3H, t, J=7.32 Hz). The absolute stereochemistry of Example 24Awas not determined.

Example 24BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 24) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(second to elute, enantiomer B) as a brown oil. LC-MS (M+H)⁺=533.3. ¹HNMR (500 MHz, MeOD) δ ppm 7.59-7.70 (2H, m), 7.16-7.27 (4H, m),7.11-7.16 (1H, m), 7.03 (2H, t, J=8.70 Hz), 4.29-4.37 (1H, m), 4.09-4.18(1H, m), 3.83-3.92 (1H, m), 3.73-3.81 (1H, m), 3.61 (3H, s), 3.16-3.27(1H, m), 3.06-3.16 (1H, m), 2.50-2.61 (1H, m, J=12.74, 8.58, 8.58, 3.97Hz), 1.80-2.10 (6H, m), 1.42-1.55 (1H, m), 0.97 (3H, t, J=7.48 Hz). Theabsolute stereochemistry of Example 24B was not determined.

Example 254-(4-amino-4-methylpiperidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

tert-butyl1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ylcarbamate(Preparation Hg) (363 mg, 0.787 mmol) in and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (229 mg,1.024 mmol) were combined and purified as per Example 16 to give4-(4-amino-4-methylpiperidin-1-yl)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (66.5 mg, 0.100 mmol, 12.76% yield) as a slightly yellow solid.LC-MS (M+H)⁺=548.2. ¹H NMR (500 MHz, MeOD) δ ppm 7.82 (1H, d, J=2.14Hz), 7.68 (1H, s), 7.20-7.27 (3H, m), 7.17 (1H, d, J=8.55 Hz), 7.00-7.09(3H, m), 4.15-4.33 (4H, m), 3.58 (3H, s), 3.44-3.56 (2H, m), 3.02-3.21(2H, m), 2.61 (1H, dd, J=8.55, 4.27 Hz), 2.01 (1H, dd, J=12.51, 8.24Hz), 1.81-1.91 (4H, m), 1.38-1.48 (2H, m).

Example 26N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

To a solution of2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Hh) (144 mg, 0.518 mmol) in Dioxane (2469 μL) was added3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation C) (100mg, 0.518 mmol), Tris(dibenzylideneacetone)dipalladium(0) (23.74 mg,0.026 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (30.0 mg,0.052 mmol), Na2CO3 (82 mg, 0.778 mmol), and water (494 μL). Theresulting mixture was heated to 110° C. and stirred overnight. Thereaction was then diluted with water (10 mL) and extracted with EtOAc(3×5 mL). The combined organic extracts were washed with brine (10 mL),dried over MgSO₄, filtered and concentrated in vacuo. Purification byprep HPLC (C18, 50×250 mm, MeOH/H₂O/TFA) gaveN²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA (170 mg, 0.311 mmol, 59.9% yield). LC-MS (M+H)⁺=434.2. ¹H NMR (500MHz, CDCl₃) δ ppm 8.06 (1H, s), 7.96 (1H, dd, J=12.51, 2.14 Hz),7.48-7.59 (2H, m), 7.26-7.33 (2H, m), 7.09-7.18 (2H, m), 4.46-4.54 (1H,m), 3.17 (3H, s), 2.87-2.97 (1H, m), 2.74-2.85 (2H, m), 2.40 (3H, s),2.09-2.21 (1H, m).

Example 26AN²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 26) was separated by multiple chiral prep HPLC injections (OJ-H30×250 mm, 10 μM, EtOH/Heptane) to giveN²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA (first to elute, enantiomer A) as a clear, colorless glass. LC-MS(M+H)⁺=434.2. ¹H NMR (500 MHz, MeOD) δ ppm 8.03-8.13 (2H, m), 7.41-7.47(2H, m), 7.23-7.30 (2 H, m), 7.04-7.14 (2H, m), 4.33 (1H, t, J=7.93 Hz),3.12 (3H, s), 2.81-2.92 (1H, m), 2.67-2.81 (2H, m), 2.40 (3H, s). Theabsolute stereochemistry of Example 26A was not determined.

Example 26BN²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 26) was separated by multiple chiral prep HPLC injections (OJ-H30×250 mm, 10 μM, EtOH/Heptane) to giveN²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA (second to elute, enantiomer B) as a clear, colorless glass. LC-MS(M+H)⁺=434.2. ¹H NMR (500 MHz, MeOD) δ ppm 8.03-8.10 (2H, m), 7.43-7.48(2H, m), 7.24-7.30 (2 H, m), 7.06-7.14 (2H, m), 4.37 (1H, t, J=7.78 Hz),3.14 (3H, s), 2.83-2.92 (1H, m), 2.69-2.80 (2H, m), 2.40 (3H, s),2.05-2.16 (1H, m). The absolute stereochemistry of Example 26B was notdetermined.

Example 271-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol

1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol(Preparation Hi) (245 mg, 0.610 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (177 mg,0.793 mmol) were combined and purified as per Example 16 to give1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol,TFA (first to elute, diastereomer A) (51.4 mg, 0.073 mmol) as a clear,colorless glass. LC-MS (M+H)⁺=589.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.97(1H, s), 7.67 (1H, s), 7.17-7.26 (3H, m), 7.14 (1H, d, J=8.55 Hz), 7.04(2 H, t, J=8.70 Hz), 6.91 (1H, d, J=8.55 Hz), 4.14 (2H, t, J=8.85 Hz),3.93-4.06 (3H, m), 3.58-3.68 (3H, m), 3.21-3.31 (1H, m), 3.09-3.21 (1H,m), 2.51-2.63 (1H, m), 2.28-2.41 (1H, m), 2.16 (1H, dd, J=12.82, 6.41Hz), 1.95 (1H, dq, J=12.82, 8.55 Hz). The relative stereochemisty ofExample 27 was not determined.

Example 27A1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol

1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol(Example 12) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂) to give1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol(first to elute, enantiomer A) (11.34 mg, 0.019 mmol) as an opaqueglass. LC-MS (M+H)⁺=589.1. The absolute stereochemistry of Example 27Awas not determined.

Example 281-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol

1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol(Preparation Hi) (245 mg, 0.610 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (177 mg,0.793 mmol) were combined and purified as per Example 16 to give1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol,TFA (second to elute, diastereomer 2) (51.1 mg, 0.073 mmol) as a whitesolid. LC-MS (M+H)⁺=589.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.96 (1H, d,J=1.83 Hz), 7.68 (1H, d, J=1.53 Hz), 7.19-7.27 (3H, m), 7.15 (1H, d,J=8.55 Hz), 7.04 (2H, t, J=8.70 Hz), 6.95 (1H, dd, J=8.55, 2.14 Hz),4.10-4.21 (2H, m), 3.95-4.04 (3H, m), 3.61-3.69 (3H, m), 3.27-3.32 (1H,m), 3.08-3.20 (1H, m), 2.57 (1H, dddd, J=13.16, 8.74, 8.62, 4.58 Hz),2.37 (1H, dt, J=12.89, 9.88 Hz), 2.18 (1H, dd, J=12.82, 6.41 Hz),1.93-2.05 (1H, m). The relative stereochemistry of Example 28 was notdetermined.

Example 28A1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol

1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol(Example 28) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 45% MeOH (0.1% DEA)/CO₂) to give1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol(first to elute, enantiomer A) (17.18 g, 29.2 mmol) as an opaque glass.LC-MS (M+H)⁺=589.1. The absolute stereochemistry of Example 28A was notdetermined.

Example 29N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N,N-dimethylpyrrolidin-3-amine(Preparation Hj) (109 mg, 0.302 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (67.6 mg,0.302 mmol) were combined and purified as per Example 26 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (88 mg, 0.133 mmol, 44.0% yield) as a scrapable tan glass. LC-MS(M+H)⁺=548.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.79 (1H, s), 7.38-7.44 (2H,m), 7.29-7.36 (3H, m), 7.24-7.29 (1H, m), 7.11-7.19 (2H, m), 4.39-4.51(2H, m), 4.28 (1H, br. s.), 4.05-4.17 (2H, m), 4.00 (1H, d, J=2.44 Hz),3.86 (3H, s), 3.22-3.47 (2H, m), 3.02 (3H, s), 2.76 (1H, br. s.), 2.60(1H, br. s.), 2.39 (1H, br. s.), 2.13 (1H, br. s.).

Example 29AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 29) was separated first by multiple chiral HPLC injections(OJ-H 30×250 mm, 30% EtOH/Heptane) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, diastereomer A) which was then separated by multiplechiral SFC injections (IB 30×250 mm, 5 μM, 35% 50:50 MeOH:MeCN/(0.1%DEA)CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, enantiomer A) as a clear, colorless glass. LC-MS(M+H)⁺=548.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.83 (1H, d, J=2.14 Hz), 7.67(1H, d, J=1.22 Hz), 7.18-7.26 (3H, m), 7.15 (1H, d, J=8.55 Hz),7.00-7.10 (3H, m), 4.00-4.16 (3H, m), 3.69-3.80 (1H, m), 3.58-3.66 (3H,m), 3.52 (1H, t, J=9.31 Hz), 3.26-3.31 (1H, m), 3.06-3.17 (1H, m),2.83-2.94 (1H, m), 2.49-2.61 (1H, m, J=13.08, 8.64, 8.64, 4.43 Hz), 2.35(6H, s), 2.21-2.30 (1H, m), 1.83-2.03 (2H, m), 1.33-1.41 (1H, m). Theabsolute stereochemistry of Example 29A was not determined.

Example 29BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 29) was separated first by multiple chiral HPLC injections(OJ-H 30×250 mm, 30% EtOH/Heptane) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(first to elute, diastereomer A) which was then separated by multiplechiral SFC injections (IB 30×250 mm, 5 M, 35% 50:50 MeOH:MeCN/(0.1%DEA)CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(second to elute, enantiomer B) as a clear, colorless glass. LC-MS(M+H)⁺=548.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.85 (1H, d, J=2.14 Hz), 7.67(1H, d, J=1.53 Hz), 7.17-7.24 (3H, m), 7.12-7.17 (1H, m), 6.99-7.08 (3H,m), 3.99-4.18 (3H, m), 3.68-3.79 (1H, m), 3.58 (3H, s), 3.48-3.56 (1H,m), 3.21-3.30 (1H, m), 3.10-3.21 (1H, m), 2.81-2.94 (1H, m), 2.49-2.62(1H, m), 2.36 (6H, s), 2.21-2.31 (1H, m), 1.82-1.99 (2H, m). Theabsolute stereochemistry of Example 29B was not determined.

Example 30N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

2-chloro-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation Hk) (109 mg, 0.314 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (70.3 mg,0.314 mmol) were combined and purified as per Example 26 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (104 mg, 0.160 mmol, 51.1% yield) as a scrapable tan glass. LC-MS(M+H)⁺=534.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.79 (1H, s), 7.52 (1H, s),7.26-7.36 (4H, m), 7.08-7.16 (3H, m), 4.41 (1H, t, J=8.09 Hz), 3.73 (3H,s), 3.37-3.63 (7H, m), 3.09-3.28 (3H, m), 2.97-3.03 (3H, m), 2.67-2.79(1H, m), 2.05-2.20 (1H, m).

Example 30AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 30) was separated by multiple chiral prep HPLC injections (OJ-H30×250 mm, 10 μM, 30% EtOH/Heptane) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (first to elute, enantiomer A) (21.6 mg, 0.033 mmol) as a scrapabletan glass. LC-MS (M+H)⁺=534.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.77 (1H,br. s.), 7.69 (1H, s), 7.23-7.31 (3H, m), 7.21 (1H, d, J=8.55 Hz),6.99-7.15 (3H, m), 4.27 (1H, t, J=8.39 Hz), 3.61-3.78 (1H, m), 3.56 (3H,s), 3.38-3.53 (3H, m), 3.23-3.38 (5H, m), 3.03-3.21 (2H, m), 2.98 (3H,s), 2.67 (1H, dt, J=8.47, 4.16 Hz), 1.99-2.13 (1H, m). The absolutestereochemistry of Example 30A was not determined.

Example 30BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopentaNJ pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 30) was separated by multiple chiral prep HPLC injections (OJ-H30×250 mm, 10 μM, 30% EtOH/Heptane) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (second to elute, enantiomer B) (21.6 mg, 0.033 mmol) as a scrapabletan glass. LC-MS (M+H)⁺=534.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.81 (1H, d,J=2.14 Hz), 7.68 (1H, d, J=1.53 Hz), 7.22-7.29 (3H, m), 7.16-7.21 (1H,m), 7.00-7.11 (3H, m), 4.24 (1H, t, J=8.55 Hz), 3.57-3.70 (1H, m), 3.53(3H, s), 3.46 (3H, br. s.), 3.27-3.36 (5H, m), 3.02-3.18 (2H, m), 2.98(3H, s), 2.60-2.72 (1H, m), 2.00-2.10 (1H, m). The absolutestereochemistry of Example 30B was not determined.

Example 31N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

Intermediate 31-1

tert-butyl4-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

tert-butyl4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(Preparation H1) (117 mg, 0.270 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (60.4 mg,0.270 mmol) were combined as per Example 26 to give tert-butyl4-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(104 mg, 0.168 mmol, 62.1% yield) crude without purification. LC-MS(M+H)⁺=620.4.

Example 31

To a solution of tert-butyl4-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(Intermediate 31-1) (167 mg, 0.270 mmol) in DCM (5 mL) was added TFA(500 μL, 6.49 mmol). The reaction mixture was stirred at RT for 1 h. Themixture was then concentrated in vacuo. Purification by prep HPLC(Waters Sunfire C18, 50×250 mm, MeOH/H₂O/TFA) gaveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (39 mg, 0.062 mmol, 22.78% yield) as a brown oil. LC-MS(M+H)⁺=520.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.83 (1H, br. s.), 7.28-7.46(5H, m), 7.08-7.21 (3H, m), 4.41-4.53 (1H, m), 4.18-4.28 (4H, m), 3.80(3H, s), 3.44 (5H, d, J=4.27 Hz), 3.24-3.31 (1H, m), 3.12-3.23 (1H, m),2.69-2.82 (1H, m), 2.06-2.22 (1H, m).

Example 32N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-(methylamino)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

Intermediate 32-1

tert-butyl1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-ylmethyl)carbamate

tert-butyl1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate(Preparation Hm) (148 mg, 0.331 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (74.1 mg,0.331 mmol) were combined as per Example 26 to give the crude tert-butyl1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate(104 mg, 0.164 mmol, 49.5% yield) which was used without furtherpurification. LC-MS (M+H)⁺=634.4.

Example 32

tert-butyl1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate(Intermediate 32-1) (210 mg, 0.331 mmol) was deprotected and purified asper Example 31 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-(methylamino)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (50 mg, 0.077 mmol, 23.31% yield) as a brown oil. LC-MS(M+H)⁺=534.4. ¹H NMR (500 MHz, MeOD) δ ppm 7.43 (1H, s), 7.40 (1H, d,J=8.55 Hz), 7.29-7.35 (3H, m), 7.24 (1H, dt, J=8.62, 2.25 Hz), 7.16 (2H,t, J=8.09 Hz), 4.47 (1H, br. s.), 4.23-4.35 (1H, m), 4.12 (3H, br. s.),4.02 (1H, br. s.), 3.84-3.91 (3H, m), 3.18-3.49 (2H, m), 2.84 (3H, s),2.68-2.81 (1H, m), 2.56 (1H, br. s.), 2.35 (1H, br. s.), 2.07-2.22 (1H,m).

Example 33N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-(methylamino)azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

Intermediate 33-1

tert-butyl1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate

tert-butyl1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate(Preparation Hn) (147 mg, 0.340 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (76 mg,0.340 mmol) were combined as per Example 26 to give the crude tert-butyl1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate(104 mg, 0.168 mmol, 49.4% yield) which was used without furtherpurification. LC-MS (M+H)⁺=620.4.

Example 33

tert-butyl1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate(Intermediate 33-1) (211 mg, 0.340 mmol) was deprotected and purified asper Example 31 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-(methylamino)azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (126 mg, 0.199 mmol, 58.5% yield) as a slightly yellow oil. LC-MS(M+H)⁺=520.4. ¹H NMR (500 MHz, MeOD) δ ppm 7.80 (1H, s), 7.55 (1H, d,J=2.14 Hz), 7.31-7.40 (2H, m), 7.26-7.31 (2H, m), 7.09-7.20 (3H, m),4.64 (2H, br. s.), 4.46 (1H, t, J=7.93 Hz), 4.21-4.36 (1H, m), 3.87 (3H,s), 3.37 (2H, s), 3.11-3.21 (1H, m), 3.04 (1H, t, J=14.95 Hz), 2.80-2.84(3H, m), 2.68-2.80 (1H, m), 2.14 (1H, dddd, J=13.28, 8.85, 6.56, 6.41Hz).

Example 34N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N,N-dimethylazetidin-3-amine(Preparation Ho) (146 mg, 0.421 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (94 mg,0.421 mmol) were combined and purified as per Example 26 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (104 mg, 0.160 mmol, 38.1% yield) as a slightly brown gum. LC-MS(M+H)⁺=534.4. ¹H NMR (500 MHz, MeOD) δ ppm 7.82 (1H, d, J=1.53 Hz), 7.48(1H, d, J=2.14 Hz), 7.39 (1H, d, J=8.55 Hz), 7.35 (1H, d, J=1.53 Hz),7.29-7.33 (2H, m), 7.21 (1H, dd, J=8.55, 2.14 Hz), 7.11-7.18 (2H, m),4.83 (4H, br. s.), 4.43-4.51 (1H, m), 4.30-4.37 (1H, m), 3.88 (3H, s),3.12-3.22 (1H, m), 3.04 (1H, d, J=6.10 Hz), 2.99 (6H, s), 2.72-2.84 (1H,m, J=13.47, 8.98, 8.98, 4.58 Hz), 2.14 (1H, dddd, J=13.16, 8.96, 6.56,6.41 Hz).

Example 35N²-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Hh) (164 mg, 0.591 mmol) and3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation B) (113mg, 0.591 mmol) were combined and purified as per Example 26 to giveN²-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA (104 mg, 0.190 mmol, 32.2% yield) as a white solid. LC-MS(M+H)⁺=434.3. ¹H NMR (500 MHz, MeOD) δ ppm 8.75 (1H, d, J=2.44 Hz), 7.94(1H, dd, J=13.28, 2.29 Hz), 7.79 (1H, t, J=8.70 Hz), 7.48 (1H, dt,J=8.85, 1.22 Hz), 7.27-7.35 (2H, m), 7.10-7.19 (2H, m), 4.51 (1H, d,J=2.44 Hz), 3.18 (3H, s), 2.89-2.98 (1H, m), 2.74-2.87 (2H, m), 2.46(3H, s), 2.09-2.23 (1H, m).

Example 36N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

Diasteriomer A

To a solution of2-chloro-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(Preparation Hp1)(30.5 mg, 0.091 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A)(26.4 mg,0.118 mmol) in THF (272 μL) was added AcOH (272 μL). The solution washeated at 100° C. overnight.

Removed solvent and took residue up in MeOH. Purified by PREP HPLC:(50×250 mm HPLC Sunfire C18 10 μm 0 to 100% A:B over 40 min, 10 min at100% B (A is 90:10:0.1 water:MeOH:TFA; B is 90:10:0.1 MeOH:water:TFA)).Speedvac'd appropriate fractions to affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine.LC-MS (M+H)⁺=523.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.74 (1H, d, J=2.14Hz), 7.49 (1H, d, J=1.53 Hz), 7.12-7.19 (2H, m), 7.05 (1H, d, J=8.24Hz), 6.95-7.01 (4H, m), 6.84 (1H, dd, J=8.55, 2.44 Hz), 5.35 (1H, td,J=52.87, 3.17 Hz), 4.07-4.17 (2 H, m), 4.04 (1H, t, J=9.61 Hz),3.80-3.94 (2H, m), 3.58 (3H, s), 3.25 (1H, ddd, J=14.19, 9.00, 4.58 Hz),3.05-3.14 (1H, m), 2.55 (1H, dddd, J=13.24, 8.74, 8.55, 4.58 Hz),2.32-2.43 (1H, m), 2.03-2.19 (1H, m), 1.93-2.02 (1H, m).

Example 37N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

Diastereomer B

The method of Example 36 was used to combine Preparation Hp2 and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine.LC-MS (M+H)⁺=523.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.76 (1H, d, J=1.83Hz), 7.48 (1H, s), 7.16 (2H, dd, J=8.24, 5.49 Hz), 6.97-7.06 (4H, m),6.92 (1H, s), 6.80 (1H, dd, J=8.39, 1.98 Hz), 5.27-5.42 (1H, m),4.00-4.17 (3H, m), 3.80-3.94 (2H, m), 3.53 (3H, s), 3.19-3.26 (1H, m),3.08-3.17 (1H, m), 2.52-2.61 (1H, m), 2.32-2.43 (1H, m), 2.02-2.18 (1H,m), 1.94 (1H, dq, J=12.97, 8.60 Hz).

Example 38N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

Diasteriomeric Mixture

The method of Example 36 was used to combine Preparation Hq and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amineas a mixture of diasteriomers. LC-MS (M+H)⁺=523.2. ¹H NMR (500 MHz,MeOD) δ ppm 7.87 (1H, s), 7.46-7.57 (1H, m), 7.36-7.43 (2H, m),7.30-7.36 (2H, m), 7.24-7.30 (1H, m), 7.11-7.18 (2H, m), 5.34-5.57 (1H,m), 4.33-4.52 (2H, m), 4.07-4.26 (2H, m), 3.93-4.01 (1H, m), 3.90 (3H,s), 3.39-3.50 (1H, m), 3.23-3.31 (1H, m), 2.67-2.80 (1H, m), 2.21-2.54(2H, m), 2.07-2.18 (1H, m).

Examples 38A and 38BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

Individual Diasteriomers

The method of Example 36 was used to combine Preparation Hq and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to afforda mixture of two diasteriomers. After preparative chiral chromatography(25% MeOH, 0.1% DEA; OD-H chiral 30×250 nm column), the twodiasteriomers were isolated.

38A: LC-MS (M+H)⁺=523.2. ¹H NMR (500 MHz, MeOD) δ ppm 7.84 (1H, d,J=2.14 Hz), 7.68 (1H, d, J=1.53 Hz), 7.19-7.24 (3H, m), 7.16 (1H, d,J=8.55 Hz), 6.99-7.09 (3H, m), 5.29-5.45 (1H, m), 4.05-4.17 (3H, m),3.80-3.99 (2H, m), 3.64 (3H, s), 3.13 (1H, dt, J=14.65, 7.32 Hz),2.51-2.61 (1H, m, J=13.12, 8.70, 8.70, 4.58 Hz), 2.28-2.38 (1H, m),2.09-2.27 (1H, m), 1.98 (1H, dddd, J=13.20, 8.62, 6.87, 6.71 Hz).

38B: LC-MS (M+H)⁺=523.2. ¹H NMR (500 MHz, MeOD) δ ppm 7.86 (1H, d,J=2.14 Hz), 7.67 (1H, s), 7.18-7.24 (3H, m), 7.15 (1H, d, J=8.55 Hz),7.00-7.07 (3H, m), 5.29-5.45 (1H, m), 4.03-4.18 (3H, m), 3.80-4.00 (2H,m), 3.60 (3H, s), 3.23-3.31 (1H, m), 3.13-3.21 (1H, m), 2.52-2.61 (1H,m), 2.28-2.39 (1H, m), 2.07-2.26 (1H, m), 1.88-1.99 (1H, m).

Example 39N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4,4-difluoropiperidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

The method of Example 36 was used to combine Preparation Hr and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4,4-difluoropiperidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 39). LC-MS (M+H)⁺=555.0. ¹H NMR (500 MHz, MeOD) δ ppm 7.68 (1H,d, J=1.83 Hz), 7.55-7.59 (2H, m), 7.18 (2H, dd, J=8.55, 5.49 Hz),7.07-7.13 (2H, m), 6.95-7.03 (3H, m), 4.16 (1H, t, J=8.39 Hz), 3.90 (4H,t, J=5.34 Hz), 3.57 (3H, s), 2.97-3.13 (2H, m), 2.56-2.66 (1H, m,J=12.78, 8.49, 8.49, 3.81 Hz), 1.95-2.14 (5H, m).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 39A and 39B, which had identical spectral data.

Example 40N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4-fluoro-5,6-dihydropyridin-1(2H)-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

The method of Example 36 was used to combine Preparation Hs and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4-fluoro-5,6-dihydropyridin-1(2H)-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 40). LC-MS (M+H)⁺=535.0. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.72(1H, d, J=1.83 Hz), 7.49 (1H, d, J=1.53 Hz), 7.13-7.19 (2H, m), 7.05(1H, d, J=8.55 Hz), 6.97-7.02 (3H, m), 6.95 (1H, s), 6.77 (1H, dd,J=8.55, 2.14 Hz), 5.31 (1H, dt, J=14.80, 2.80 Hz), 4.18-4.33 (2H, m),4.15 (1H, t, J=8.55 Hz), 3.99-4.06 (1H, m), 3.80-3.88 (1H, m), 3.51 (3H, s), 2.98-3.12 (2H, m), 2.58 (1H, dddd, J=12.63, 8.55, 8.43, 3.66 Hz),2.37-2.53 (2 H, m), 1.99 (1H, dq, J=12.86, 8.33 Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 40A and 40B, which had identical spectral data.

Example 41N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

The method of Example 36 was used to combine Preparation Ht and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 41).

The mixture of a pair of racemic diasteriomers were separated by chiralchromatography followed by reverse-phase chromatography to afford theindividual enantiomers Examples 41A, 41B, 41C, and 41D.

41A: LC-MS (M+H)⁺=573.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.84 (1H, d,J=1.53 Hz), 7.49 (1H, s), 7.15 (2H, dd, J=8.39, 5.34 Hz), 7.04 (1H, d,J=8.24 Hz), 6.95-7.02 (4H, m), 6.72 (1H, dd, J=8.39, 1.98 Hz), 4.11 (1H,t, J=8.39 Hz), 3.94-4.08 (2H, m), 3.78-3.91 (2H, m), 3.56 (3H, s),3.18-3.27 (1H, m), 2.97-3.14 (2H, m), 2.50-2.62 (1H, m, J=12.86, 8.60,8.60, 4.12 Hz), 2.17-2.34 (2H, m), 1.91-2.02 (1H, m).

41B: LC-MS (M+H)⁺=573.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.84 (1H, br.s.), 7.48 (1H, d, J=1.53 Hz), 7.11-7.22 (2H, m), 6.95-7.09 (5H, m),6.69-6.78 (1H, m), 4.12 (1H, t, J=8.55 Hz), 3.95-4.08 (2H, m), 3.77-3.92(2H, m), 3.55 (3H, s), 3.21 (1H, ddd, J=14.11, 8.93, 3.51 Hz), 2.98-3.16(2H, m), 2.51-2.65 (1H, m), 2.16-2.35 (2H, m), 1.90-2.04 (1H, m).

41C: LC-MS (M+H)⁺=573.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.84 (1H, br.s.), 7.48 (1H, d, J=1.53 Hz), 7.11-7.22 (2H, m), 6.95-7.09 (5H, m),6.69-6.78 (1H, m), 4.12 (1H, t, J=8.55 Hz), 3.95-4.08 (2H, m), 3.77-3.92(2H, m), 3.55 (3H, s), 3.21 (1H, ddd, J=14.11, 8.93, 3.51 Hz), 2.98-3.16(2H, m), 2.51-2.65 (1H, m), 2.16-2.35 (2H, m), 1.90-2.04 (1H, m).

41D: LC-MS (M+H)⁺=573.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.84 (1H, d,J=1.53 Hz), 7.49 (1H, s), 7.15 (2H, dd, J=8.39, 5.34 Hz), 7.04 (1H, d,J=8.24 Hz), 6.95-7.02 (4H, m), 6.72 (1H, dd, J=8.39, 1.98 Hz), 4.11 (1H,t, J=8.39 Hz), 3.94-4.08 (2H, m), 3.78-3.91 (2H, m), 3.56 (3H, s),3.18-3.27 (1H, m), 2.97-3.14 (2H, m), 2.50-2.62 (1H, m, J=12.86, 8.60,8.60, 4.12 Hz), 2.17-2.34 (2H, m), 1.91-2.02 (1H, m).

Example 42N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-(3-ethoxypropyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The method of Example 36 was used to combine Preparation Hu and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to affordN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-(3-ethoxypropyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 42). LC-MS (M+H)⁺=537.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.91(1H, d, J=2.14 Hz), 7.48 (1H, d, J=1.53 Hz), 7.12-7.19 (2H, m), 7.03(1H, d, J=8.55 Hz), 6.94-7.01 (4H, m), 6.74 (1H, dd, J=8.55, 2.14 Hz),5.45 (1H, t, J=4.73 Hz), 4.14-4.21 (1H, m), 3.61-3.71 (4H, m), 3.46-3.57(5H, m), 2.63 (2H, dd, J=8.85, 6.41 Hz), 1.96-2.05 (1H, m), 1.93 (2H,quin, J=5.72 Hz), 1.25 (3H, t, J=7.02 Hz).

Example 433-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)propan-1-ol

The method of Example 36 was used to combine Preparation Hy and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to afford3-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)propan-1-ol(Example 43). LC-MS (M+H)⁺=509.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.87 (1H,d, J=2.14 Hz), 7.68 (1H, d, J=1.53 Hz), 7.19-7.26 (3H, m), 7.16 (1H, d,J=8.55 Hz), 7.01-7.09 (3H, m), 4.19 (1H, t, J=8.09 Hz), 3.64-3.72 (4H,m), 3.61 (3H, s), 2.77-2.86 (1H, m), 2.60-2.74 (2H, m), 1.96-2.06 (1H,m), 1.90 (2H, qd, J=6.46, 6.26 Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 43A and 43B, which had identical spectral data.

Example 447-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

To a solution of2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Hh) (141.2 mg, 0.508 mmol) and3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation D) (208mg, 1.017 mmol) in N-Methyl-2-pyrrolidinone (4067 μL) was added H₂SO₄(43.4 μL, 0.813 mmol). The solution was heated to 100° C. When thereaction was complete, water and NaHCO₃ were added. After extractioninto CH₂Cl₂, the organic extracts were dried over MgSO₄, filtered, andconcentrated in vacuo. Applied the residue to SG and eluted with aEtOAc/Hex gradient, which yielded7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 44).

LC-MS (M+H)⁺=446.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.43 (1H, br. s.),8.47 (1H, s), 7.77 (1H, br. s.), 7.54 (1H, d, J=8.85 Hz), 7.14-7.20 (2H,m), 6.99 (2H, t, J=8.55 Hz), 4.88 (1H, br. s.), 4.24-4.31 (1H, m), 3.71(3H, s), 3.15 (3H, d, J=4.90 Hz), 2.73-2.82 (1H, m), 2.63-2.72 (2H, m),2.46 (3H, s), 2.06-2.16 (1H, m).

The racemic material above was separated by SFC chiral chromatography toobtain the individual enantiomers (Examples 44A and 44B). SFC Method:Chiralpak OJ-H (30×150 mm), 30% methanol (0.1% diethylamine) in CO₂, 100bar, flow rate 50 mL/min for 12 min, absorbance 268 nm, injection 2.0 mLof 10 mg/mL solution in methanol, t_(R) (peak A)=4.7 min, t_(R) (peak B)9.6 min. The absolute stereochemistry of individual enantiomers(Examples 44A and 44B) was not determined

44A: LC-MS (M+H)⁺=446.2. LC R_(t) 13.03 min (Waters Sunfire 4.6×150 mm10 to 100% B in A over 15 min, 1.5 mL/min. (A is 90:10:0.1water:MeOH:TFA; B is 90:10:0.1 MeOH:water:TFA)). ¹H NMR (500 MHz,DMSO-d6) δ ppm 9.22 (1H, s), 8.58 (1H, s), 8.18 (1H, s), 7.30 (1H, d,J=8.85 Hz), 7.22 (2H, t, J=6.26 Hz), 7.08-7.16 (3H, m), 6.93-6.99 (1H,m), 4.17 (1H, t, J=8.09 Hz), 3.63 (3H, s), 2.97 (3H, d, J=4.27 Hz),2.72-2.81 (1H, m), 2.53-2.66 (2H, m), 2.31 (3H, s), 1.85-1.95 (1H, m).13C NMR (126 MHz, DMSO-d6) δ ppm 170.7, 160.7 (d, J=241.3 Hz), 159.7,159.6, 159.2, 151.4, 145.0, 142.9, 140.4 (d, J=2.7 Hz), 129.8 (d, J=7.8Hz, 2C), 124.6, 117.9, 114.9 (d, J=20.9 Hz, 2C), 109.6, 108.1, 101.5,55.2, 50.4, 32.7, 27.4, 25.4, 13.5. [α]_(D) −69.13° (c 2.67, CHCl₃).

Example 45N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The method of Example 7 was used to combine Preparation Hw and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to affordN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 45). The mixture of a pair of racemic diasteriomers wereseparated by chiral chromatography followed by reverse-phasechromatography to afford the individual enantiomers Examples 45A, 45B,45C, and 45D.

45A: LC-MS (M+H)⁺=549.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 10.75 (1H, br.s.), 7.40 (1H, d, J=8.24 Hz), 7.22-7.29 (3H, m), 7.15-7.21 (3H, m),6.99-7.08 (2 H, m), 5.97 (1H, d, J=8.24 Hz), 4.42-4.50 (1H, m), 3.84(3H, s), 3.78 (1H, t, J=8.09 Hz), 3.63 (2H, br. s.), 3.43 (3H, s),2.86-2.97 (1H, m), 2.82 (2H, t, J=8.55 Hz), 2.21-2.32 (1H, m), 1.15-1.27(1H, m), 0.62-0.70 (1H, m), 0.53-0.62 (1H, m), 0.39 (1H, ddd, J=9.46,5.19, 4.88 Hz), 0.26-0.33 (1H, m)

45B: LC-MS (M+H)⁺=549.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 10.58 (1H, br.s.), 7.40 (1H, d, J=8.85 Hz), 7.22-7.29 (3H, m), 7.14-7.20 (3H, m), 7.04(2H, t, J=8.39 Hz), 6.02 (1H, d, J=8.24 Hz), 4.45 (1H, d, J=3.66 Hz),3.84 (3H, s), 3.71-3.79 (1H, m), 3.63 (2H, d, J=3.05 Hz), 3.42 (3H, s),2.91 (1H, d, J=9.46 Hz), 2.79 (2H, dd, J=8.70, 5.34 Hz), 2.21-2.31 (1H,m), 1.19 (1H, dt, J=8.55, 4.27 Hz), 0.62-0.70 (1H, m), 0.54-0.62 (1H,m), 0.39 (1H, dq, J=9.54, 4.86 Hz), 0.24-0.33 (1H, m).

45C: LC-MS (M+H)⁺=549.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 10.75 (1H, br.s.), 7.40 (1H, d, J=8.24 Hz), 7.22-7.29 (3H, m), 7.15-7.21 (3H, m),6.99-7.08 (2 H, m), 5.97 (1H, d, J=8.24 Hz), 4.42-4.50 (1H, m), 3.84(3H, s), 3.78 (1H, t, J=8.09 Hz), 3.63 (2H, br. s.), 3.43 (3H, s),2.86-2.97 (1H, m), 2.82 (2H, t, J=8.55 Hz), 2.21-2.32 (1H, m), 1.15-1.27(1H, m), 0.62-0.70 (1H, m), 0.53-0.62 (1H, m), 0.39 (1H, ddd, J=9.46,5.19, 4.88 Hz), 0.26-0.33 (1H, m).

45D: LC-MS (M+H)⁺=549.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 10.58 (1H, br.s.), 7.40 (1H, d, J=8.85 Hz), 7.22-7.29 (3H, m), 7.14-7.20 (3H, m), 7.04(2H, t, J=8.39 Hz), 6.02 (1H, d, J=8.24 Hz), 4.45 (1H, d, J=3.66 Hz),3.84 (3H, s), 3.71-3.79 (1H, m), 3.63 (2H, d, J=3.05 Hz), 3.42 (3H, s),2.91 (1H, d, J=9.46 Hz), 2.79 (2H, dd, J=8.70, 5.34 Hz), 2.21-2.31 (1H,m), 1.19 (1H, dt, J=8.55, 4.27 Hz), 0.62-0.70 (1H, m), 0.54-0.62 (1H,m), 0.39 (1H, dq, J=9.54, 4.86 Hz), 0.24-0.33 (1H, m).

Example 46N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-7-(4-fluorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(268 mg, 0.919 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (205 mg, 0.919 mmol) inTHF (1 mL) and acetic acid (1.000 mL). The reaction mixture was stirredovernight at 75° C. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (60.7 mg, 0.095 mmol, 10.36% yield). LC-MS (M+H)⁺=479.4. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.64-11.83 (1H, m), 7.62 (1H, d, J=1.5 Hz), 7.39(2H, d, J=2.1 Hz), 7.22 (1H, d, J=5.2 Hz), 7.15 (1H, d, J=8.5 Hz),6.96-7.07 (3H, m), 5.29 (1H, s), 4.29-4.38 (1H, m), 3.81 (3H, s),3.50-3.57 (1H, m), 3.43-3.49 (1H, m), 3.31-3.39 (3H, m), 3.16-3.26 (2H,m), 3.09-3.14 (1H, m), 2.58-2.72 (1H, m), 2.52-2.58 (1H, m), 2.13-2.25(1H, m).

Example 46A & 46B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 46) was purified using chiral SFC to afford peak A (Example46A) and peak B (Example 46B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5μM), 35% methanol (0.1% diethylamine) in CO₂, 35° C., flow rate 2.0mL/min for 14 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solutionin methanol (multiple stacked injections), t_(R) (peak A)=4.3 min, t_(R)(peak B) 10.8 min. The absolute stereochemistry of individualenantiomers (Examples 46A and 46B) was not determined LC-MS and ¹H NMRanalytical data for the separated enantiomers was identical to theracemate (Example 46).

Example 47N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-trideuteromethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A solution of2-Chloro-7-(4-fluorophenyl)-N-trideuteromethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(47.5 mg, 0.169 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(37.8 mg, 0.169 mmol) in THF (1 mL) and acetic acid (1 mL) was heated at85° C. overnight. The product was purified by a reverse-phasepreparative HPLC method to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-trideuteromethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (33.3 mg, 0.057 mmol, 33.8% yield) as brown oil. LC-MS(M+H)⁺=467.9. ¹H NMR (500 MHz, CDCl₃) δ ppm 11.21 (1H, s), 8.35-9.96(1H, m), 8.20 (1H, s), 7.51 (1H, s), 7.43 (1H, d, J=8.5 Hz), 7.25 (1H,s), 7.22 (1H, d, J=8.9 Hz), 7.14-7.20 (2H, m), 7.01 (1H, t, J=8.5 Hz),5.98 (1H, s), 4.43 (1H, d, J=4.6 Hz), 3.85 (3H, s), 2.88 (1H, d, J=9.5Hz), 2.69-2.83 (2H, m), 2.20-2.32 (1H, m).

Example 48N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-((R)-1-methoxybutan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,2 TFA

Diasteriomeric Mixture

2-chloro-7-(4-fluorophenyl)-N—((R)-1-methoxybutan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Hx) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-((R)-1-methoxybutan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,2 TFA as a mixture of two diasteriomers (Example 48). LC-MS(M+H)⁺=537.5. ¹H NMR (500 MHz, CDCl₃) δ ppm 11.66 (br. s., 1H) 7.99 (s,1H) 7.51 (d, J=8.85 Hz, 1H) 7.32 (dd, J=8.85, 1.83 Hz, 1H) 7.18-7.30 (m,4H) 7.04 (td, J=8.62, 1.68 Hz, 2H) 5.83 (t, J=9.61 Hz, 1H) 4.43-4.51 (m,1H) 4.28-4.39 (m, 1H) 3.87 (s, 3H) 3.51-3.64 (m, 2H) 3.38-3.49 (m, 3H)2.87-3.00 (m, 1H) 2.75-2.85 (m, 2H) 2.24-2.35 (m, 1H) 1.69-1.87 (m, 2H)0.97-1.06 (m, 3H).

The mixture of two diasteriomers was separated by chiral chromatographyto afford two diasteriomers Example 48A and 48B as free amines.

Example 48A: LC-MS (M+H)⁺=537.4. ¹H NMR (500 MHz, MeOD) δ ppm 7.86 (d,J=2.14 Hz, 1H) 7.66 (d, J=1.53 Hz, 1H) 7.16-7.25 (m, 3H) 7.10-7.16 (m,1H) 6.99-7.07 (m, 3H) 4.45-4.53 (m, 1H) 4.17 (t, J=8.24 Hz, 1H) 3.61 (s,3H) 3.56 (dd, J=9.46, 5.80 Hz, 1H) 3.44-3.51 (m, 1H) 3.37 (d, J=7.02 Hz,3H) 2.76-2.86 (m, 1H) 2.59-2.75 (m, 2H) 1.94-2.04 (m, 1H) 1.73-1.85 (m,1H) 1.54-1.66 (m, 1H) 0.99 (t, J=7.48 Hz, 3H).

Example 48B: LC-MS (M+H)⁺=537.4. ¹H NMR (500 MHz, MeOD) δ ppm 7.86 (d,J=2.14 Hz, 1H) 7.67 (d, J=1.53 Hz, 1H) 7.18-7.26 (m, 3H) 7.11-7.16 (m,1H) 6.97-7.08 (m, 3H) 4.44-4.53 (m, 1H) 4.17 (t, J=8.09 Hz, 1H) 3.61 (s,3H) 3.55 (dd, J=9.46, 5.49 Hz, 1H) 3.46 (dd, J=9.61, 5.65 Hz, 1H)3.35-3.41 (m, 3H) 2.77-2.87 (m, 1H) 2.67-2.76 (m, 1H) 2.64 (ddd,J=12.44, 8.62, 3.66 Hz, 1H) 1.93-2.07 (m, 1H) 1.80 (ddd, J=13.50, 7.71,5.34 Hz, 1H) 1.56-1.68 (m, 1H) 1.01 (t, J=7.48 Hz, 3H).

Example 49N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,2 TFA

Diasteriomeric Mixture

2-chloro-N—((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Hy) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,2 TFA as a mixture of two diasteriomers (Example 49). LC-MS(M+H)⁺=519.5. ¹H ¹H NMR (500 MHz, CDCl₃) δ ppm 11.81 (s, 1H) 7.85 (s,1H) 7.38-7.48 (m, 2H) 7.28 (s, 1H) 7.26 (ddd, J=8.77, 5.11, 1.98 Hz, 1H)7.12 (d, J=1.22 Hz, 1H) 7.04 (td, J=8.62, 1.68 Hz, 2H) 5.65 (t, J=7.02Hz, 1H) 4.41-4.52 (m, 1H) 3.73-3.88 (m, 4H) 2.88-3.01 (m, 1H) 2.71-2.88(m, 2H) 2.25-2.39 (m, 1H) 1.40 (dd, J=6.56, 4.12 Hz, 3H) 0.99-1.14 (m,1H) 0.65-0.75 (m, 1H) 0.53-0.64 (m, 1H) 0.39 (tt, J=9.80, 5.00 Hz, 1H)0.27-0.35 (m, 1 H).

The mixture of two diasteriomers was separated by chiral chromatographyto afford two diasteriomers Example 49A and 49B as free amines.

Example 49A: LC-MS (M+H)⁺=519.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.87 (d,J=2.14 Hz, 1H) 7.66 (d, J=1.53 Hz, 1H) 7.17-7.28 (m, 3H) 7.08-7.17 (m,1H) 6.90-7.08 (m, 3H) 4.15 (t, J=8.24 Hz, 1H) 3.78-3.92 (m, 1H) 3.59 (s,3H) 2.75-2.85 (m, 1H) 2.59-2.74 (m, 2H) 1.33 (d, J=6.71 Hz, 3H)1.00-1.14 (m, 1H) 0.82-1.00 (m, 1H) 0.39-0.59 (m, 3H) 0.26 (dt, J=9.38,4.62 Hz, 1H).

Example 49B: LC-MS (M+H)⁺=519.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.87 (d,J=2.14 Hz, 1H) 7.66 (d, J=1.53 Hz, 1H) 7.15-7.25 (m, 3H) 7.13 (d, J=8.55Hz, 1H) 7.02 (t, J=8.85 Hz, 2H) 6.98 (dd, J=8.55, 2.14 Hz, 1H) 4.16 (t,J=8.09 Hz, 1H) 3.82-3.98 (m, 1H) 3.60 (s, 3H) 2.78-2.87 (m, 1H)2.55-2.75 (m, 2H) 1.91-2.04 (m, 1H) 1.35 (d, J=6.71 Hz, 3H) 0.79-0.98(m, 1H) 0.55 (td, J=8.70, 4.27 Hz, 1H) 0.45-0.51 (m, 1H) 0.32-0.43 (m,J=9.65, 5.04, 4.86, 4.86 Hz, 1H) 0.16-0.29 (m, 1H).

Example 50N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((S)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA

Diasteriomeric Mixture

2-chloro-N—((S)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Hz) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((S)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA as a mixture of two diasteriomers (Example 50). LC-MS (M+H)⁺=519.5.¹H NMR (500 MHz, CDCl₃) δ ppm 11.84 (s, 1H) 7.80 (s, 1H) 7.43 (s, 1H)7.41 (d, J=8.85 Hz, 1H) 7.28 (s, 1H) 7.26 (ddd, J=8.70, 5.19, 1.98 Hz,1H) 7.19 (d, J=8.55 Hz, 1H) 7.11 (s, 1H) 7.04 (td, J=8.62, 1.68 Hz, 2H)5.66 (t, J=6.87 Hz, 1H) 4.40-4.52 (m, 1H) 3.72-3.87 (m, 4H) 2.87-3.07(m, 1H) 2.67-2.86 (m, 2H) 2.26-2.40 (m, 1H) 1.40 (dd, J=6.56, 4.12 Hz, 3H) 1.03-1.15 (m, 1H) 0.56-0.76 (m, 2H) 0.29-0.49 (m, 2H).

The mixture of two diasteriomers was separated by chiral chromatographyto afford two diasteriomers Example 50A and 50B as free amines.

Example 50A: LC-MS (M+H)⁺=519.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.88 (d,J=2.14 Hz, 1H) 7.67 (d, J=1.53 Hz, 1H) 7.17-7.24 (m, 3H) 7.14 (d, J=8.55Hz, 1H) 6.90-7.08 (m, 3H) 4.18 (t, J=8.09 Hz, 1H) 3.88 (dd, J=8.09, 6.56Hz, 1H) 3.61 (s, 3H) 2.77-2.89 (m, 1H) 2.58-2.77 (m, 2H) 1.90-2.05 (m,1H) 1.35 (d, J=6.71 Hz, 3H) 1.07 (dt, J=8.24, 4.88 Hz, 1H) 0.51-0.57 (m,1H) 0.44-0.51 (m, 1H) 0.40 (dd, J=9.61, 4.73 Hz, 1H) 0.17-0.29 (m, 1H).

Example 50B: LC-MS (M+H)⁺=519.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.87 (d,J=1.83 Hz, 1H) 7.67 (s, 1H) 7.20-7.27 (m, 3H) 7.14 (d, J=8.55 Hz, 1H)6.93-7.08 (m, 3H) 4.17 (t, J=8.24 Hz, 1H) 3.75-3.93 (m, 1H) 3.61 (s, 3H)2.76-2.88 (m, 1H) 2.54-2.73 (m, 2H) 1.89-2.08 (m, 1H) 1.34 (d, J=6.71Hz, 3H) 0.99-1.12 (m, 1H) 0.54-0.63 (m, 1H) 0.46-0.54 (m, 1H) 0.43 (dd,J=9.61, 4.73 Hz, 1H) 0.18-0.28 (m, 1H).

Example 51N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

2-chloro-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Ia) (125 mg, 0.453 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (101 mg,0.453 mmol) were combined and purified as per Example 26 to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (178 mg, 0.309 mmol, 68.1% yield) as a slightly yellow, scrapableglass. LC-MS (M+H)⁺=463.2. ¹H NMR (500 MHz, MeOD) δ ppm 7.81 (1H, s),7.62 (1H, s), 7.32-7.47 (7H, m), 7.14 (1H, dd, J=8.55, 2.14 Hz),4.54-4.72 (2H, m), 4.19 (1H, dd, J=11.44, 4.73 Hz), 4.10 (1H, t, J=4.43Hz), 3.94 (1H, dd, J=11.44, 4.73 Hz), 3.86 (3H, s), 3.15-3.19 (3H, m).

Example 51AN²-(4-(4-chloro-1H-imiazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

N²-(4-(4-chloro-1H-imiazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamineExample 51 was separated by multiple chiral prep HPLC injections (OJ-H30×250 mm, 10 μM, EtOH/Heptane) to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (first to elute, enantiomer A) (36.5 mg, 0.063 mmol) as a yellowsolid. LC-MS (M+H)⁺=463.2. ¹H NMR (500 MHz, MeOD) δ ppm 7.83 (1H, br.s.), 7.70 (1H, br. s.), 7.35 (2H, t, J=7.32 Hz), 7.24-7.33 (4H, m), 7.21(1H, d, J=8.55 Hz), 6.97-7.05 (1H, m), 4.52-4.71 (2H, m), 4.16 (1H, dd,J=11.44, 4.73 Hz), 3.98 (1H, br. s.), 3.87-3.96 (1H, m), 3.61 (3H, br.s.), 3.06-3.14 (3H, m). The absolute stereochemistry of Example 51A wasnot determined.

Example 51BN²-(4-(4-chloro-1H-imiazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

N²-(4-(4-chloro-1H-imiazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamineExample 51 was separated by multiple chiral prep HPLC injections (OJ-H30×250 mm, 10 μM, EtOH/Heptane) to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (second to elute, enantiomer B) (30.9 mg, 0.054 mmol) as a yellowsolid. LC-MS (M+H)⁺=463.2. ¹H NMR (500 MHz, MeOD) δ ppm 7.74 (2H, br.s.), 7.24-7.48 (7H, m), 7.01-7.13 (1H, m), 4.52-4.73 (2H, m), 4.17 (1H,dd, J=11.44, 4.73 Hz), 4.00-4.11 (1H, m), 3.88-4.00 (1H, m), 3.71 (3H,br. s.), 3.12 (3H, s). The absolute stereochemistry of Example 51B wasnot determined.

Example 52N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

To a solution of2-chloro-N-ethyl-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(146 mg, 0.481 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(107 mg, 0.481 mmol) in THF (1.0 mL) and acetic acid (1.0 mL). Thereaction mixture was stirred overnight at 75° C. The crude reactionmixture was purified by preparative HPLC. The appropriate fractions wereevaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA salt (59.9 mg, 0.092 mmol, 93% yield). LC-MS (M+H)⁺=491.4. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.77 (1H, s), 7.67 (1H, d, J=1.5 Hz), 7.39 (1H,dd, J=8.5, 2.1 Hz), 7.26-7.35 (5H, m), 7.16 (1H, s), 7.14 (1H, s), 7.06(1H, d, J=1.5 Hz), 4.75-4.90 (2H, m), 4.14-4.23 (2H, m), 3.90 (1H, d,J=7.0 Hz), 3.81 (3H, s), 3.62 (2H, s), 3.27 (3H, s), 1.34 (3H, t, J=7.2Hz).

Examples 52A & 52B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N⁴,N⁴-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine(55.0 mg, 0.112 mmol) (Example 52) was purified using chiral SFC toafford peak A (17.2 mg, 0.035 mmol) (Example 52A) and peak B (18.8 mg,0.038 mmol) (Example 52B). SFC Method: Chiralpak OJ-H (30×250 mm, 5 μM),35% methanol (0.1% diethylamine) in CO₂, 35° C., flow rate 70 mL/min for13 min, absorbance 268 nm, injection 5 μL of 27 mg/mL solution inmethanol (multiple stacked injections), t_(R) (peak A)=4.2 min, t_(R)(peak B) 8.3 min. The absolute stereochemistry of individual enantiomers(Examples 52A and 52B) was not determined LC-MS and ¹H NMR analyticaldata for the separated enantiomers was identical to the racemate(Example 52).

Example 53N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

To a solution of2-chloro-N,N-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(135 mg, 0.466 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(104 mg, 0.466 mmol) in THF (1.0 mL) and acetic acid (1.0 mL). Thereaction mixture was stirred overnight at 75° C. The crude reactionmixture was purified by preparative HPLC. The appropriate fractions wereevaporated to affordN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA salt (80.1 mg, 0.130 mmol, 96% yield). LC-MS (M+H)⁺=477.3. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.74 (1H, s), 7.74 (1H, d, J=1.5 Hz), 7.36 (1H,s), 7.34-7.26 (6H, m), 7.15 (1H, d, J=8.2 Hz), 7.07 (1H, d, J=1.5 Hz),4.83 (1H, m), 4.13-4.21 (1H, m), 3.81 (3H, s), 3.47 (3H, s), 3.32 (6H,s).

Examples 53A & 53B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(80.1 mg, 0.130 mmol) (Example 53) was purified using chiral SFC toafford peak A (21.2 mg, 0.044 mmol) (Example 53A) and peak B (24.2 mg,0.051 mmol) (Example 53B). SFC Method: Chiralpak OJ-H (30×250 mm, 5 μM),35% methanol (0.1% diethylamine) in CO₂, 35° C., flow rate 70 mL/min for13 min, absorbance 268 nm, injection 5 μL of 27 mg/mL solution inmethanol (multiple stacked injections), t_(R) (peak A)=4.5 min, t_(R)(peak B) 9.5 min. The absolute stereochemistry of individual enantiomers(Examples 53A and 53B) was not determined LC-MS and ¹H NMR analyticaldata for the separated enantiomers was identical to the racemate(Example 53).

Example 548-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation D (0.076 g, 0.38 mmol), Preparation Ja (0.11g, 0.38 mmol), Na₂CO₃ (0.079 g, 0.75 mmol) and xantphos (0.216 g, 0.38mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.17 g, 0.18 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diatomaceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (50 mL×2). The combined organic layer waswashed with brine solution (25 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC to give8-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(0.08 g, 47%) as off-white solid. LC-MS (M+H)⁺=462.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 8.70 (1H, s), 7.8 (1H, m), 7.5 (1H, m), 7.34 (2H, m),7.21 (4H, m), 7.13 (1H, m), 4.60 (1H, d, J=14.0 Hz), 4.46 (1H, d, J=14.0Hz), 3.83 (2H, m), 3.78 (1H, m), 3.75 (3H, s), 3.01 (3H, d, J=4.0 Hz),2.32 (3H, s,).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 54A and 54B, which had identical spectral data.

Example 55N4-ethyl-8-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation D (0.085 g, 0.40 mmol), Preparation Jb (0.16g, 0.52 mmol), Na₂CO₃ (0.11 g, 1.0 mmol) and xantphos (0.30 g, 0.52mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.26 g, 0.26 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diatomaceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (10 mL×3). The combined organic layer waswashed with brine solution (10 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC to giveN4-ethyl-8-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(0.90 g, 40%) as off-white solid. LC-MS (M+H)⁺=476.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 8.69 (1H, s), 7.73 (1H, s), 7.48 (1H, s), 7.34 (2H, m),7.21-7.13 (3H, m), 4.62 (1H, d, J=14.0 Hz), 4.47 (1H, d, J=14.0 Hz),4.07 (2H, m), 3.92 (2H, m), 3.82 (3H, s), 3.54 (3H, m), 2.33 (3H, s),1.22 (3H, t, J=7.2.0 Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 55A and 55B, which had identical spectral data.

Example 56N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.70 g, 0.32 mmol), Preparation Jb (0.11 g,0.35 mmol), Na₂CO₃ (0.07 g, 0.71 mmol) and xantphos (0.20 g, 0.35 mmol)in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.18 g, 0.17 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (50 mL×2). The combined organic layer was washed withbrine solution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(0.70 g, 40%) as off-white solid. LC-MS (M−H)⁺=495.2. ¹H NMR (400 MHz,-DMSO-d6): δ ppm 9.91 (1H, sb), 7.83 (1H, m), 7.69 (1H, s), 7.39 (1H,s), 7.22 (4H, m), 7.10 (4H, m), 4.65 (1H, d, J=14.0 Hz), 4.48 (1H, d,J=14.0 Hz), 4.04 (1H, m), 3.83 (1H, m), 3.74 (3H, s), 3.54 (2H, m), 1.22(3H, t, J=7.2.0 Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 56A and 56B, which had identical spectral data.

Example 57AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine

A solution of Preparation A (0.051 g, 0.23 mmol), Preparation Jc1 (0.09g, 0.25 mmol), Na₂CO₃ (0.050 g, 0.51 mmol) and xantphos (0.148 g, 0.25mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.132 g, 0.12 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (50 mL×2). The combined organic layer was washed withbrine solution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (60-120 mesh) using 10% methanol indichloromethane as mobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine(0.030 g, 18%) as an off-white solid.

LC-MS (M+H)⁺=539.0. ¹H NMR (400 MHz, DMSO-d6): δ ppm 9.19 (1H, s), 7.89(1H, s), 7.74 (1H, s), 7.43 (1H, s), 7.27 (2H, m), 7.18-7.11 (4H, m),5.42 (1H, m), 5.04 (1H, d, J=13.6 Hz), 4.81 (1H, d, J=13.6 Hz), 4.13(2H, m), 3.91-3.77 (4H, m), 3.66 (1H, m), 3.58 (3H, s), 2.23 (2H, m).

Example 57BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine

A solution of Preparation A (0.062 g, 0.28 mmol), Preparation Jc2 (0.110g, 0.31 mmol), Na₂CO₃ (0.066 g, 0.62 mmol) and xantphos (0.181 g, 0.31mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.162 g, 0.15 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diatomaceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (50 mL×2). The combined organic layer waswashed with brine solution (50 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by column chromatography (60-120 mesh) using 8%methanol in dichloromethane as mobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine(0.031 g, 19%) as an off-white solid. LC-MS (M+H)⁺=539.0. ¹H NMR (400MHz, DMSO-d6): δ ppm 9.21 (1H, s), 7.87 (1H, s), 7.74 (1H, s), 7.43 (1H,s), 7.24 (2H, m), 7.16-7.09 (4H, m), 5.36 (1H, m), 4.95 (2H, m), 5.05(1H, m), 3.95-3.80 (2H, m), 3.78-3.70 (4H, m), 3.6 (3H, s), 2.22 (2H,m).

Example 58AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine

A solution of Preparation A (0.057 g, 0.28 mmol), Preparation Jd1 (0.10g, 0.28 mmol), Na₂CO₃ (0.06 g, 0.56 mmol) and xantphos (0.16 g, 0.28mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.14 g, 0.14 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diatomaceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (50 mL×2). The combined organic layer waswashed with brine solution (25 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by column chromatography (60-120 mesh) using 10%methanol in dichloromethane as mobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine(0.040 g, 27%) as off-white solid. LC-MS (M+H)⁺=539.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.45 (1H, sb), 7.79 (1H, s), 7.71 (1H, m), 7.47 (1H, s),7.34-7.26 (2H, m), 7.21-7.12 (4H, m), 5.41 (1H, m), 5.07 (1H, d, J=14.0Hz), 4.85 (1H, d, J=14.0 Hz), 4.53-4.38 (2H, m), 4.32-4.30 (4H, m),3.89-3.64 (4H, m), 2.50-2.58 (2H, m).

Example 58BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine

A solution of Preparation A (0.062 g, 0.282 mmol), Preparation Jd2 (0.11g, 0.310 mmol), Na₂CO₃ (0.065 g, 0.620 mmol) and xantphos (0.179 g,0.310 mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.16 g, 0.155 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (25 mL×3). The combined organic layer was washed withbrine solution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (60-120 mesh) using 10% methanol indichloromethane as mobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine(0.040 g, 27%) as off-white solid. LC-MS (M+H)⁺=539.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.39 (1H, sb), 7.78 (1H, s), 7.71 (1H, m), 7.46 (1H, s),7.28-7.13 (6H, m), 5.40 (1H, m), 4.94 (2H, m), 4.04-3.95 (4H, m), 3.83(3H, m), 3.67 (3H, m), 2.33-2.08 (2H, m).

Example 59N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

The method of example 56 was used to combine Preparation C andPreparation Jb to affordN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine.LC-MS (M+H)⁺=464.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.99-8.06 (2H, m),7.24-7.34 (4H, m), 7.04 (2H, t, J=8.70 Hz), 4.65 (1H, d, J=14.30 Hz),4.56 (1H, d, J=14.30 Hz), 4.16 (1H, dd, J=11.29, 4.58 Hz), 3.94-4.00(1H, m), 3.92 (1H, t, J=4.88 Hz), 3.57 (2H, q, J=7.12 Hz), 2.37 (3H, s),1.29 (3H, t, J=7.17 Hz)

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 59A and 59B, which had identical spectral data.

Example 60N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.15 g, 0.61 mmol), Preparation Ja (0.20 g,0.61 mmol), Na₂CO₃ (0.144 g, 1.31 mmol) and xantphos (0.39 g, 0.61 mmol)in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.31 g, 0.32 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (25 mL×2). The combined organic layer was washed withbrine solution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (Silica gel, 60-120 mesh) using 50% ethylacetate in pet-ether as mobile phase to give to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(0.12 g, 37%) as off-white solid. LC-MS (M−H)⁺=479.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 12.02 (1H, sb), 9.17 (1H, s), 8.06 (1H, s), 7.73 (1H,s), 7.41 (1H, s), 7.25-7.08 (5H, m), 6.77 (1H, m), 4.57 (1H, d, J=14.4Hz), 4.44 (1H, d, J=14.4 Hz), 4.02 (1H, m), 3.89 (1H, m), 3.80 (1H, m),3.3 (3H, s), 2.93 (3H, d, J=4.0 Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 60A and 60B, which had identical spectral data.

Example 61N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4,N4-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.15 g, 0.70 mmol), Preparation Je (0.24 g,0.78 mmol), Na₂CO₃ (0.16 g, 1.56 mmol) and xantphos (0.45 g, 0.78 mmol)in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.35 g, 0.39 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (30 mL×2). The combined organic layer was washed withbrine solution (20 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby Combiflash (Silica 120 g) using 50% ethyl acetate in pet-ether asmobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4,N4-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(0.15 g, 47%) as off-white solid. LC-MS (M−H)⁺=493.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.21 (1H, s), 7.91 (1H, s), 7.73 (1H, s), 7.41 (1H, s),7.24 (2H, m), 7.14 (4H, m), 4.83 (1H, d, J=13.6 Hz), 4.70 (1H, d, J=13.6Hz), 4.16 (1H, m), 4.10 (1H, m), 3.72 (1H, m), 3.56 (3H, s), 3.06 (6H,s).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 61A and 61B, which had identical spectral data.

Example 62N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.13 g, 0.61 mmol), Preparation Jf (0.20 g,0.61 mmol), Na₂CO₃ (0.13 g, 1.2 mmol) and xantphos (0.36 g, 0.61 mmol)in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.28 g, 0.31 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (30 mL×2). The combined organic layer was washed withbrine solution (20 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby Combiflash (Silica 120 g) using 50% ethyl acetate in pet-ether asmobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(0.097 g, 47%) as off-white solid. LC-MS (M+H)⁺=509.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.17 (1H, s), 7.83 (1H, s), 7.72 (1H, s), 7.40 (1H, s),7.24 (2H, m), 7.12 (4H, m), 4.78 (1H, d, J=13.6 Hz), 4.65 (1H, d, J=13.6Hz), 4.09 (1H, m), 3.73 (1H, m), 3.55 (1H, m), 3.54 (3H, s), 3.38 (2H,m), 3.02 (3H, s), 1.20 (3H, t, J=6.9.0 Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 62A and 62B, which had identical spectral data.

Example 63N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine

A solution of Preparation A (0.082 g, 0.31 mmol), Preparation Jg (0.13g, 0.31 mmol), Na₂CO₃ (0.077 g, 0.72 mmol) and xantphos (0.21 g, 0.31mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.16 g, 0.12 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (30 mL×2). The combined organic layer was washed withbrine solution (20 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby Combiflash (Silica 120 g) using 50% ethyl acetate in pet-ether asmobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine(0.070 g, 35%) as off-white solid. LC-MS (M−H)⁺=541.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.41 (1H, s), 7.88 (1H, s), 7.73 (1H, s), 7.41 (1H, s),7.25 (2H, m), 7.17-7.08 (4H, m), 4.78-4.63 (6H, m), 4.04 (2H, m), 3.78(1H, m), 3.50 (3H, s).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 63A and 63B, which had identical spectral data.

Example 64N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

2-chloro-8-(4-chlorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Kb) (116 mg, 0.374 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (84 mg,0.374 mmol) were combined and purified as per Example 26 to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (105 mg, 0.172 mmol, 45.9% yield) as a white solid. LC-MS(M+H)⁺=497.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.86 (1H, br. s.), 7.63 (1H,br. s.), 7.30-7.46 (6H, m), 7.19 (1H, dd, J=8.55, 2.14 Hz), 4.62-4.73(1H, m), 4.56 (1H, d, J=14.65 Hz), 4.11-4.20 (1H, m), 4.07 (1H, d,J=3.36 Hz), 3.94 (1H, dd, J=11.44, 3.81 Hz), 3.82-3.89 (3H, m),3.10-3.20 (3H, m).

Example 64AN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 64) was separated by multiple chiral HPLC injections (OJ-H30×250 mm, 10 μM, 35% EtOH/Hexanes) to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (first to elute, enantiomer A) (35 mg, 0.057 mmol) as an off-whitesolid. LC-MS (M+H)⁺=497.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.80 (1H, s),7.71 (1H, s), 7.36 (2H, d, J=8.24 Hz), 7.25-7.30 (3H, m), 7.22 (1H, d,J=8.55 Hz), 7.03 (1H, d, J=8.55 Hz), 4.50-4.68 (2H, m), 4.15 (1H, dd,J=11.29, 4.27 Hz), 3.97 (1H, t, J=4.27 Hz), 3.87-3.94 (1H, m), 3.66 (3H,s), 3.08 (3H, s). The absolute stereochemistry of Example 64A was notdetermined.

Example 64BN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 64) was separated by multiple chiral HPLC injections (OJ-H30×250 mm, 10 μM, 35% EtOH/Hexanes) to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (second to elute, enantiomer B) (29 mg, 0.047 mmol) as an off-whitesolid. LC-MS (M+H)⁺=497.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.78 (1H, s),7.72 (1H, d, J=1.53 Hz), 7.34-7.39 (2H, m), 7.26-7.31 (3H, m), 7.24 (1H,d, J=8.55 Hz), 7.04 (1H, dd, J=8.55, 2.14 Hz), 4.51-4.68 (2H, m), 4.15(1H, dd, J=11.29, 4.58 Hz), 3.98 (1H, t, J=4.43 Hz), 3.91 (1H, dd,J=11.44, 4.73 Hz), 3.68 (3H, s), 3.09 (3H, s). The absolutestereochemistry of Example 64B was not determined.

Example 65N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

2-chloro-8-(4-chlorophenyl)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Kc) (125 mg, 0.386 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (86 mg,0.386 mmol) were combined and purified as per Example 26 to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (110 mg, 0.176 mmol, 45.6% yield) as a white solid. LC-MS(M+H)⁺=511.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.92 (1H, br. s.), 7.31-7.51(7H, m), 7.16 (1H, dd, J=8.39, 1.98 Hz), 4.91-5.05 (2H, m), 4.12-4.30(2H, m), 3.76-3.91 (4H, m), 3.34-3.44 (6H, m).

Example 65AN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 65) was separated by multiple chiral HPLC injections (OJ-H30×250 mm, 10 μM, 35% EtOH/Hexanes) to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (first to elute, enantiomer A) (35 mg, 0.056 mmol) as an off-whitesolid. LC-MS (M+H)⁺=511.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.71 (1H, d,J=1.22 Hz), 7.67 (1H, s), 7.36 (2H, d, J=8.55 Hz), 7.24-7.30 (3H, m),7.22 (1H, d, J=8.55 Hz), 7.01 (1H, dd, J=8.55, 2.14 Hz), 4.77-4.96 (2H,m), 4.23 (1H, dd, J=11.44, 5.65 Hz), 4.11 (1H, t, J=5.65 Hz), 3.84 (1H,dd, J=11.60, 6.10 Hz), 3.60-3.66 (3H, m), 3.18-3.23 (6H, m). Theabsolute stereochemistry for Example 65A was not determined.

Example 65BN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 65) was separated by multiple chiral HPLC injections (OJ-H30×250 mm, 10 μM, 35% EtOH/Hexanes) to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (second to elute, enantiomer B) (34 mg, 0.054 mmol) as an off-whitesolid. LC-MS (M+H)⁺=511.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.73 (1H, d,J=1.53 Hz), 7.63 (1H, s), 7.38 (2H, d, J=8.55 Hz), 7.22-7.33 (4H, m),7.03 (1H, dd, J=8.55, 2.14 Hz), 4.81-4.97 (2H, m), 4.24 (1H, dd,J=11.44, 5.65 Hz), 4.13 (1H, t, J=5.49 Hz), 3.85 (1H, dd, J=11.44, 5.95Hz), 3.68 (3H, s), 3.24 (6H, s). The absolute stereochemistry forExample 65B was not determined.

Example 66N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine

2-chloro-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Ka) (125 mg, 0.336 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (75 mg,0.336 mmol) were combined and purified as per Example 26 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine,TFA (40 mg, 0.059 mmol, 17.69% yield) as a white solid. LC-MS(M+H)⁺=559.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.83 (1H, br. s.), 7.39-7.45(3H, m), 7.31-7.39 (4H, m), 7.17 (1H, dd, J=8.55, 2.14 Hz), 4.88-4.97 (5H, m), 4.74-4.81 (1H, m), 4.08-4.19 (2H, m), 3.91 (1H, dd, J=11.44, 3.81Hz), 3.81 (3H, s).

Example 66AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine(Example 66) was separated by multiple chiral SFC injections (OD-H30×250 mm, 5 μM, 35% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine(first to elute, enantiomer A) (7.8 mg, 0.014 mmol) as a white solid.LC-MS (M+H)⁺=559.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.76 (1H, s), 7.66 (1H,s), 7.31 (2 H, d, J=8.24 Hz), 7.20-7.27 (3H, m), 7.10-7.16 (1H, m), 6.97(1H, d, J=8.55 Hz), 4.68-4.83 (2H, m), 4.55-4.66 (4H, m), 4.16 (1H, dd,J=11.44, 5.04 Hz), 4.02 (1H, t, J=4.88 Hz), 3.88 (1H, dd, J=11.29, 5.80Hz), 3.49 (3H, s). The absolute stereochemistry of Example 66A was notdetermined.

Example 66BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine

N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine(Example 66) was separated by multiple chiral SFC injections (OD-H30×250 mm, 5 μM, 35% MeOH (0.1% DEA)/CO₂) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine(second to elute, enantiomer B) (8.1 mg, 0.014 mmol) as a white solid.LC-MS (M+H)⁺=559.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.76 (1H, d, J=2.14Hz), 7.67 (1H, d, J=1.53 Hz), 7.29-7.34 (2H, m), 7.19-7.27 (3H, m), 7.13(1H, d, J=8.55 Hz), 6.97 (1H, dd, J=8.55, 2.14 Hz), 4.67-4.84 (2H, m),4.60 (4H, t, J=12.21 Hz), 4.17 (1H, dd, J=11.44, 5.04 Hz), 4.02 (1H, t,J=5.19 Hz), 3.88 (1H, dd, J=11.29, 5.80 Hz), 3.46-3.51 (3H, m). Theabsolute stereochemistry of 66B was not determined.

Example 678-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

2-chloro-8-(4-chlorophenyl)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Kc) (128 mg, 0.395 mmol) and3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation C) (76mg, 0.395 mmol) were combined and purified as per Example 26 to give8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (120 mg, 0.202 mmol, 51.2% yield) as a white solid. LC-MS(M+H)⁺=480.1. ¹H NMR (500 MHz, MeOD) δ ppm 8.07 (1H, s), 7.80 (1H, dd,J=12.36, 2.29 Hz), 7.54 (1H, t, J=8.55 Hz), 7.40-7.47 (3H, m), 7.34-7.40(2H, m), 4.90-5.04 (2H, m), 4.22-4.28 (1H, m), 4.20 (1H, br. s.), 3.87(1H, dd, J=11.44, 5.34 Hz), 3.39 (6H, s), 2.40 (3H, s).

Example 67A8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

8-(4-chlorophenyl)-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 67) was separated by multiple chiral SFC injections (AD-H30×250 mm, 5 μM, 40% MeOH (0.1% DEA)/CO₂) to give8-(4-chlorophenyl)-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(first to elute, enantiomer A) (25.8 mg, 0.054 mmol) as an opaque glass.LC-MS (M+H)⁺=480.1. ¹H NMR (400 MHz, MeOD) δ ppm 7.99 (1H, s), 7.87-7.95(1H, m), 7.19-7.33 (6H, m), 4.72-4.83 (2H, m), 4.22 (1H, dd, J=11.33,5.54 Hz), 4.02 (1H, t, J=5.67 Hz), 3.87-3.95 (1H, m), 3.09 (6H, s), 2.33(3H, s). The absolute stereochemistry of Example 67A was not determined.

Example 67B8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 67) was separated by multiple chiral SFC injections (AD-H30×250 mm, 5 μM, 40% MeOH (0.1% DEA)/CO₂) to give8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(second to elute, enantiomer B) (25.8 mg, 0.054 mmol) as an opaqueglass. LC-MS (M+H)⁺=480.1. ¹H NMR (400 MHz, MeOD) δ ppm 7.99 (1H, s),7.87-7.94 (1H, m), 7.20-7.31 (6H, m), 4.72-4.84 (2H, m), 4.22 (1H, dd,J=11.33, 5.54 Hz), 4.02 (1H, t, J=5.79 Hz), 3.92 (1H, dd, J=11.33, 6.04Hz), 3.09 (6H, s), 2.33 (3H, s). The absolute stereochemistry of Example67B was not determined.

Example 688-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine

2-chloro-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Ka) (128 mg, 0.344 mmol) and3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation C) (66.1mg, 0.344 mmol) were combined and purified as per Example 26 to give8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine,TFA (120 mg, 0.187 mmol, 54.4% yield) as a white solid. LC-MS(M+1-1)⁺=528.1. ¹H NMR (500 MHz, MeOD) δ ppm 8.01-8.10 (1H, m),7.75-7.85 (1H, m), 7.25-7.50 (6H, m), 4.70-4.96 (6H, m), 4.13-4.24 (1H,m), 4.02-4.13 (1H, m), 3.96 (1H, dd, J=11.44, 4.73 Hz), 2.32-2.44 (3H,m).

Example 698-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

2-chloro-8-(4-chlorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Kb) (150 mg, 0.484 mmol) and3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation C) (93mg, 0.484 mmol) were combined and purified as per Example 26 to give8-(4-chlorophenyl)-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (120 mg, 0.207 mmol, 42.8% yield) as a clear, colorless glass. LC-MS(M+H)⁺=466.1. ¹H NMR (500 MHz, MeOD) δ ppm 8.08 (1H, s), 7.89-7.96 (1H,m), 7.57 (1H, t, J=8.55 Hz), 7.47-7.52 (1H, m), 7.42-7.46 (2H, m),7.34-7.40 (2H, m), 4.53-4.74 (2H, m), 4.18 (1H, dd, J=11.44, 4.43 Hz),4.07-4.13 (1H, m), 3.95 (1H, dd, J=11.44, 4.12 Hz), 3.17 (3H, s), 2.42(3H, s).

Example 69A8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 69) was separated by multiple chiral SFC injections (AD-H30×250 mm, 5 μM, 20% MeOH (0.1% DEA)/CO₂) to give8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(first to elute, enantiomer A) (52.4 mg, 0.112 mmol) as a white solid.LC-MS (M+H)⁺=466.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.97-8.13 (2H, m),7.17-7.41 (6H, m), 4.48-4.72 (2H, m), 4.17 (1H, dd, J=11.29, 4.58 Hz),3.98 (1H, dd, J=11.44, 5.04 Hz), 3.93 (1H, d, J=4.88 Hz), 2.99-3.08 (3H,m), 2.35-2.42 (3H, m). The absolute stereochemistry of Example 69A wasnot determined.

Example 69B8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 69) was separated by multiple chiral SFC injections (AD-H30×250 mm, 5 μM, 20% MeOH (0.1% DEA)/CO₂) to give8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(second to elute, enantiomer B) (45.9 mg, 0.099 mmol) as a white solid.LC-MS (M+H)⁺=466.1. ¹H NMR (500 MHz, MeOD) δ ppm 8.00-8.06 (2H, m),7.25-7.35 (6H, m), 4.52-4.68 (2H, m), 4.17 (1H, dd, J=11.29, 4.88 Hz),3.96-4.02 (1H, m), 3.92 (1H, t, J=4.88 Hz), 3.05 (3H, s), 2.38 (3H, s).The absolute stereochemistry of Example 69B was not determined.

Example 708-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

2-chloro-8-(4-chlorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Kb) (105.5 mg, 0.340 mmol) and3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (Preparation E) (69.1 mg,0.340 mmol) were combined and purified as per Example 26 to give8-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (120 mg, 0.203 mmol, 59.7% yield) as a clear, colorless glass. LC-MS(M+H)⁺=477.2. ¹H NMR (500 MHz, MeOD) δ ppm 9.11 (1H, s), 7.76 (1H, br.s.), 7.51-7.59 (2 H, m), 7.34-7.46 (4H, m), 7.26-7.33 (1H, m), 4.52-4.75(2H, m), 4.17 (1H, dd, J=11.44, 4.43 Hz), 4.08 (1H, br. s.), 3.88-4.04(4H, m), 3.17 (3H, s), 2.44 (3H, s).

Example 70A8-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

8-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 70) was separated by multiple chiral SFC injections (AD-H30×250 mm, 5 μM, 20% MeOH (0.1% DEA)/CO₂) to give8-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(first to elute, enantiomer A) as an opaque yellow glass. LC-MS(M+H)⁺=477.2. ¹H NMR (500 MHz, MeOD) δ ppm 7.84 (1H, d, J=2.14 Hz), 7.62(1H, br. s.), 7.30 (2H, d, J=8.55 Hz), 7.19-7.28 (2H, m), 7.06-7.15 (1H,m), 6.94 (2H, dd, J=8.55, 2.14 Hz), 4.48-4.67 (2H, m), 4.06-4.18 (1H,m), 3.84-3.96 (2H, m), 3.54 (3H, s), 3.04 (3H, s), 2.22 (3H, s). Theabsolute stereochemistry of Example 70A was not determined.

Example 70B8-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

8-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 70) was separated by multiple chiral SFC injections (AD-H30×250 mm, 5 μM, 20% MeOH (0.1% DEA)/CO₂) to give8-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(second to elute, enantiomer B) as an opaque yellow glass. LC-MS(M+H)⁺=477.2. ¹H NMR (500 MHz, MeOD) δ ppm 7.85 (1H, d, J=2.14 Hz),7.60-7.64 (1H, m), 7.27-7.32 (2H, m), 7.19-7.24 (2H, m), 7.06-7.11 (1H,m), 6.90-6.96 (2H, m), 4.48-4.64 (2H, m), 4.06-4.14 (1H, m), 3.84-3.92(2H, m), 3.51-3.57 (3H, m), 3.01-3.06 (3H, m), 2.19-2.25 (3H, m). Theabsolute stereochemistry of Example 70B was not determined.

Example 718-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

2-chloro-8-(4-chlorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Kb) (105.5 mg, 0.340 mmol) and3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation D)(69.5 mg, 0.340 mmol) were combined and purified as per Example 26 togive8-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (120 mg, 0.203 mmol, 59.6% yield) as a clear, colorless glass. LC-MS(M+H)⁺=478.2. ¹H NMR (500 MHz, MeOD) δ ppm 8.85 (1H, s), 7.67 (1H, d,J=8.55 Hz), 7.64 (1H, s), 7.41-7.48 (2H, m), 7.33-7.40 (2H, m), 7.18(1H, dd, J=8.55, 2.14 Hz), 4.52-4.73 (2H, m), 4.17 (1H, dd, J=11.44,4.42 Hz), 4.08 (1H, br. s.), 3.94 (1H, dd, J=11.60, 3.97 Hz), 3.91 (3H,s), 3.17 (3H, s), 2.45 (3H, s).

Example 71A8-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

8-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 71) was separated by multiple chiral SFC injections (OD-H30×250 mm, 5 μM, 35% MeOH (0.1% DEA)/CO₂) to give8-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(first to elute, enantiomer A) (24 mg, 0.050 mmol) as a scrapable tanglass. LC-MS (M+H)⁺=478.2. ¹H NMR (500 MHz, MeOD) δ ppm 8.57 (1H, s),7.93 (1H, d, J=2.14 Hz), 7.37 (1H, d, J=8.85 Hz), 7.29-7.34 (2H, m),7.21-7.26 (2H, m), 6.98 (1H, dd, J=8.70, 2.29 Hz), 4.50-4.66 (2H, m),4.13 (1H, dd, J=10.68, 3.97 Hz), 3.85-3.95 (2H, m), 3.59 (3H, s), 3.05(3H, s), 2.42 (3H, s). The absolute stereochemistry of Example 71A wasnot determined.

Example 71B8-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

8-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(Example 71) was separated by multiple chiral SFC injections (OD-H30×250 mm, 5 μM, 35% MeOH (0.1% DEA)/CO₂) to give8-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine(second to elute, enantiomer B) (22 mg, 0.046 mmol) as a scrapable tanglass. LC-MS (M+H)⁺=478.2. ¹H NMR (500 MHz, MeOD) δ ppm 8.57 (1H, s),7.93 (1H, d, J=2.14 Hz), 7.36 (1H, d, J=8.55 Hz), 7.28-7.34 (2H, m),7.20-7.26 (2H, m), 6.98 (1H, dd, J=8.55, 2.14 Hz), 4.50-4.66 (2H, m),4.13 (1H, dd, J=10.68, 3.97 Hz), 3.84-3.95 (2H, m), 3.59 (3H, s), 3.04(3H, s), 2.41 (3H, s). The absolute stereochemistry of Example 71B wasnot determined.

Example 728-(4-bromophenyl)-N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

8-(4-bromophenyl)-2-chloro-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation La) (95 mg, 0.268 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (90 mg,0.402 mmol) were combined and purified as per Example 16 to give8-(4-bromophenyl)-N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (38.5 mg, 0.059 mmol, 21.91% yield) as a tan solid. LC-MS(M+H)⁺=541.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.83 (1H, br. s.), 7.70 (1H,br. s.), 7.17-7.42 (7H, m), 6.96-7.06 (1H, m), 4.52-4.72 (2H, m),4.13-4.23 (1H, m), 3.98 (1H, br. s.), 3.87-3.96 (1H, m), 3.62 (3H, d,J=7.02 Hz), 3.06-3.16 (3H, m).

Example 738-(4-bromophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

8-(4-bromophenyl)-2-chloro-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation La) (95 mg, 0.268 mmol) and3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation C) (77mg, 0.402 mmol) were combined and purified as per Example 16 to give8-(4-bromophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (23 mg, 0.037 mmol, 13.75% yield). LC-MS (M+H)⁺=510.2. ¹H NMR (500MHz, MeOD) δ ppm 7.74 (2H, br. s.), 7.25-7.45 (7H, m), 7.00-7.12 (1H,m), 4.53-4.73 (2H, m), 4.17 (1H, dd, J=11.29, 4.88 Hz), 4.00-4.09 (1H,m), 3.89-3.99 (1H, m), 3.71 (3H, br. s.), 3.12 (3H, s).

Examples 74A and 74BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-2-methylpyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine

Discrete Diasteriomers

To a mixture of(S)-2-chloro-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation Me) (192.0 mg, 0.575 mmol),4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (154 mg,0.690 mmol), XANTPHOS (33.3 mg, 0.058 mmol), Pd2(dba)₃ (26.3 mg, 0.029mmol), and Cs₂CO₃ (562 mg, 1.726 mmol) was added Dioxane (2397 μL). Themixture was flushed with Nitrogen and placed in a capped vial and heatedat 100° C. overnight.

Cooled to rt and diluted with EtOAc. Filtered through a Celite® plug androtovaped. The residue was placed on Silica Gel and eluted with anEtOAc/Hex gradient to obtain(S)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine(189 mg, 0.363 mmol, 63.1% yield) as a diasteriomeric mixture. Thediasteriomers were separated by chiral SFC chromatography (Chiralcel OJcolumn, 40% MeOH (0.1% DEA) in CO₂) to provide Examples 74A and 74B.

74A: LC-MS (M+H)⁺=521.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.60 (1H, d,J=1.53 Hz), 7.50 (1H, d, J=1.53 Hz), 7.35-7.41 (2H, m), 7.00-7.10 (4H,m), 6.93-6.99 (2H, m), 5.82 (1H, t, J=2.44 Hz), 5.42-5.48 (1H, m),5.35-5.40 (1H, m), 5.29 (1H, s), 3.72-3.79 (1H, m), 3.68 (3H, s),3.55-3.63 (1H, m), 1.97-2.14 (3H, m), 1.71-1.76 (1H, m), 1.26 (3H, d,J=6.41 Hz).

Example 75N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

To a solution of2-chloro-N-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine(Preparation Mb) in Dioxane (619 μL) and Water (124 μL) was added4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (29.1 mg,0.130 mmol), Tris(dibenzylideneacetone)dipalladium(0) (59.5 mg, 0.065mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (75 mg, 0.130mmol), and Na₂CO₃ (20.66 mg, 0.195 mmol). The resulting mixture wasbrought to 110° C. in a sealed tube and stirred overnight The reactionmixture was then diluted with EtOAc (10 mL), washed with water (5 mL),brine (5 mL), dried over MgSO₄, filtered and concentrated in vacuo.Purification by flash chromatography (Silica, MeOH/CHCl₃) removed theXanthene ligand as to not have it ppt out on the prep column.Purification of the resulting oil by prep HPLC (C18, 50×250 mm,MeOH/H₂O/TFA) gaveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine,TFA (16.94 mg, 0.028 mmol, 21.91% yield) as a clear glass. LC-MS(M+H)⁺=481.0. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.86 (1H, d, J=1.53 Hz),7.56 (1H, d, J=2.14 Hz), 7.43-7.49 (2H, m), 7.40 (1H, d, J=8.85 Hz),7.37 (1H, d, J=1.22 Hz), 7.21 (1H, dd, J=8.55, 2.14 Hz), 7.17 (2H, t,J=8.70 Hz), 6.10 (1H, t, J=3.20 Hz), 5.17 (1H, dd, J=11.44, 3.81 Hz),5.04 (1H, dd, J=11.60, 2.14 Hz), 3.86 (3H, s), 3.66 (2H, q, J=7.32 Hz),1.32 (3H, t, J=7.32 Hz).

Example 75AN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(Example 75) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 35% MeOH (0.1% DEA)/CO₂) to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(first to elute, enantiomer A) (20.7 mg, 0.043 mmol, 10.71% yield) as anoff-white, scrapable foam. LC-MS (M+H)⁺=481.0. ¹H NMR (500 MHz, MeOD) δppm 7.87 (1H, d, J=2.14 Hz), 7.68 (1H, d, J=1.22 Hz), 7.36-7.42 (2H, m),7.22 (1H, d, J=1.53 Hz), 7.13-7.17 (1H, m), 7.04-7.11 (3H, m), 5.79 (1H,d, J=2.14 Hz), 5.09-5.15 (1H, m), 4.96-5.03 (1H, m), 3.71 (3H, s), 3.57(2H, q, J=7.02 Hz), 1.25-1.30 (3H, m). The absolute stereochemistry ofExample 75A was not determined.

Example 75BN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(Example 75) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 35% MeOH (0.1% DEA)/CO₂) to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(second to elute, enantiomer B) (19.6 mg, 0.041 mmol, 10.14% yield) asan off-white, scrapable foam. LC-MS (M+H)⁺=481.0. ¹H NMR (500 MHz, MeOD)δ ppm 7.87 (1H, s), 7.68 (1H, s), 7.40 (2 H, td, J=5.80, 2.44 Hz), 7.23(1H, s), 7.14-7.18 (1H, m), 7.06-7.12 (3H, m), 5.80 (1H, br. s.), 5.13(1H, dd, J=10.99, 3.05 Hz), 5.00 (1H, d, J=10.99 Hz), 3.72 (3H, s), 3.57(2H, q, J=7.02 Hz), 1.25-1.31 (3H, m). The absolute stereochemistry ofExample 75B was not determined.

Example 76N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine

2-chloro-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation Mc1) (49 mg, 0.145 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (32.4 mg,0.145 mmol) were combined and purified as per Example 26 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine,TFA (diastereomer 1, racemate) (24.18 mg, 0.038 mmol, 26.1% yield) as aslightly yellow glass. LC-MS (M+H)⁺=525.1. ¹H NMR (500 MHz, MeOD) δ ppm7.92 (1H, d, J=1.53 Hz), 7.54 (1H, br. s.), 7.47-7.52 (2H, m), 7.38-7.42(2H, m), 7.28 (1H, dd, J=8.55, 2.14 Hz), 7.15-7.21 (2H, m), 6.07-6.11(1H, m), 5.62 (1H, dd, J=10.99, 3.97 Hz), 5.35-5.53 (2H, m), 4.09-4.23(2H, m), 3.89-4.08 (2H, m), 3.87 (3 H, s), 2.44 (1H, br. s.), 2.12-2.38(1H, m). The relative stereochemistry of Example 76 was not determined.

Example 77N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine

2-chloro-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation Mc2) (40 mg, 0.118 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (26.5 mg,0.118 mmol) were combined and purified as per Example 26 to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine,TFA (diastereomer 2, racemate) (25.75 mg, 0.040 mmol, 34.0% yield) as aslightly yellow glass. LC-MS (M+H)⁺=525.1. ¹H NMR (500 MHz, MeOD) δ ppm7.88 (1H, d, J=1.22 Hz), 7.54 (1H, s), 7.46-7.51 (2H, m), 7.36-7.42 (2H,m), 7.16-7.25 (3H, m), 6.08 (1H, t, J=3.20 Hz), 5.52-5.60 (1H, m),5.36-5.52 (2H, m), 4.02-4.20 (2H, m), 4.00 (2H, s), 3.88-3.99 (1H, m),3.86 (3H, s), 2.37-2.51 (1H, m), 2.14-2.37 (1H, m). The relativestereochemistry of Example 77 was not determined.

Example 78N⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

2-chloro-N-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine(Preparation Mb) and 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline(Preparation C) (51.6 mg, 0.268 mmol) were combined and purified as perExample 75 to giveN⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine,TFA (64.1 mg, 0.114 mmol, 42.4% yield) as a white solid. LC-MS(M+H)⁺=450.0. ¹H NMR (500 MHz, MeOD) δ ppm 8.08 (1H, s), 7.96-8.02 (1H,m), 7.42-7.53 (4H, m), 7.17 (2H, t, J=8.85 Hz), 6.04 (1H, t, J=3.05 Hz),5.18 (1H, dd, J=11.44, 3.51 Hz), 5.02-5.08 (1H, m), 3.64 (2H, q, J=7.12Hz), 2.42 (3H, s), 1.34 (3H, t, J=7.17 Hz).

Example 78AN⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

N⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(Example 78) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 30% MeOH (0.1% DEA)/CO₂) to giveN⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(first to elute, enantiomer A) (25.8 mg, 0.057 mmol, 21.40% yield) as awhite solid. LC-MS (M+H)⁺=450.0. ¹H NMR (500 MHz, MeOD) δ ppm 8.15 (1H,dd, J=13.89, 2.29 Hz), 8.03 (1H, s), 7.39-7.47 (3H, m), 7.33 (1H, t,J=8.55 Hz), 7.07-7.12 (2H, m), 5.84 (1H, t, J=2.59 Hz), 5.14 (1H, dd,J=11.29, 3.36 Hz), 5.03 (1H, dd, J=11.14, 1.68 Hz), 3.53-3.61 (2H, m),2.39 (3H, s), 1.27-1.32 (3H, m). The absolute stereochemistry of Example78A was not determined.

Example 78BN⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

N⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(Example 78) was separated by multiple chiral SFC injections (OJ-H30×250 mm, 5 μM, 30% MeOH (0.1% DEA)/CO₂) to giveN⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(second to elute, enantiomer B) (24.6 mg, 0.055 mmol, 20.40% yield) as awhite solid. LC-MS (M+H)⁺=450.0. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.99-8.06(1H, m), 7.94 (1H, s), 7.36-7.42 (2H, m), 7.23-7.29 (1H, m), 7.12 (1H,dd, J=8.55, 1.83 Hz), 7.02-7.08 (2H, m), 5.86 (1H, d, J=2.44 Hz),5.01-5.21 (2H, m), 3.50-3.60 (2H, m), 2.40 (3H, s), 1.27-1.33 (3H, m).The absolute stereochemistry of Example 78B was not determined.

Example 79AN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

2-chloro-7-(4-fluorophenyl)-N-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine(Preparation Ma) (149 mg, 0.533 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (119 mg,0.533 mmol) were combined and purified as per Example 75 to give theracemateN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diaminewhich was separated by multiple chiral SFC injections (OJ-H 30×250 mm, 5μM, 35% MeOH (0.1% DEA)/CO₂) to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(first to elute, enantiomer A) (18.3 mg, 0.039 mmol, 7.36% yield) as awhite scrapable foam. LC-MS (M+H)⁺=467.0. ¹H NMR (500 MHz, MeOD) δ ppm7.89-7.94 (1H, m), 7.65-7.69 (1H, m), 7.36-7.42 (2H, m), 7.20-7.24 (1H,m), 7.13-7.18 (1H, m), 7.03-7.12 (3H, m), 5.79 (1H, br. s.), 5.08-5.16(1H, m), 4.95-5.03 (1H, m), 3.68-3.73 (3H, m), 3.02-3.07 (3H, m). Theabsolute stereochemistry of Example 79A was not determined.

Example 79BN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine

2-chloro-7-(4-fluorophenyl)-N-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine(Preparation Ma) (149 mg, 0.533 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (119 mg,0.533 mmol) were combined and purified as per Example 75 to give theracemateN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diaminewhich was separated by multiple chiral SFC injections (OJ-H 30×250 mm, 5μM, 35% MeOH (0.1% DEA)/CO₂) to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine(second to elute, enantiomer B) (22.1 mg, 0.047 mmol, 8.89% yield) as aslightly yellow scrapable foam. LC-MS (M+H)⁺=467.0. ¹H NMR (500 MHz,MeOD) δ ppm 7.92 (1H, d, J=2.14 Hz), 7.68 (1H, d, J=1.53 Hz), 7.39 (2H,dd, J=8.70, 5.34 Hz), 7.22 (1H, d, J=1.53 Hz), 7.15 (1H, d, J=8.55 Hz),7.04-7.11 (3H, m), 5.79 (1H, br. s.), 5.12 (1H, dd, J=10.99, 3.36 Hz),4.99 (1H, d, J=10.99 Hz), 3.70 (3H, s), 3.05 (3H, s). The absolutestereochemistry of Example 79B was not determined.

Example 80N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine

A solution of Preparation A (0.102 g, 0.560 mmol), Preparation Ma (0.160g, 0.560 mmol), Na₂CO₃ (0.119 g, 0.110 mmol) and xantphos (0.325 g,0.560 mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.310 g, 0.21 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through celite bed and washed with ethyl acetate. The filtratewas evaporated under reduced pressure and the residue was diluted withwater. The aqueous solution was extracted with ethyl acetate (75 mL×2).The combined organic layer was washed with brine solution (50 mL), driedover anhydrous Na₂SO₄ and evaporated under reduced pressure to get crudecompound. The crude compound was purified by column chromatography(Silica gel, 60-120 mesh) using 21% ethyl acetate in pet-ether as mobilephase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine(0.90 g, 40%) as off-white solid. LC-MS (M+H)⁺=529.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.6 (1H, s), 7.99 (1H, s), 7.98 (1H, s), 7.76-7.41 (3H,m), 7.23-7.13 (4H, m), 5.87 (1H, s), 5.33 (1H, dd, J=11.1, 3.2 Hz), 5.17(1H, dd, J=11.1, 3.2), 4.67 (4H, m), 3.72 (3H, s).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 80A and 80B, which had identical spectral data.

Example 81N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine,TFA

Diasteriomeric Mixture

2-chloro-N—((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine(Preparation Mf) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine,TFA as a mixture of 2 diasteriomers (Example 81). LC-MS (M+H)⁺=521.3. ¹HNMR (500 MHz, MeOD) δ ppm 7.82 (d, J=1.53 Hz, 1H) 7.44-7.51 (m, 3H) 7.38(d, J=8.55 Hz, 1H) 7.35 (d, J=1.53 Hz, 1H) 7.14-7.22 (m, 3H) 6.08 (br.s., 1H) 5.21 (dd, J=11.60, 3.05 Hz, 1H) 5.07 (dd, J=11.44, 2.59 Hz, 1H)3.84 (s, 3H) 3.30 (m, 1H) 1.38 (d, J=6.41 Hz, 3H) 1.06-1.13 (m, 1H)0.59-0.66 (m, 1H) 0.54 (d, J=3.97 Hz, 1H) 0.37 (d, J=4.88 Hz, 1H) 0.28(d, J=4.88 Hz, 1H).

Example 82N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N4-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine,TFA

2-chloro-7-(4-fluorophenyl)-N-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine(Preparation Ma) was reacted as described in Example 112 with3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation C) togiveN2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N4-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine,TFA (Example 82). LC-MS (M+H)⁺=436.1. ¹H NMR (500 MHz, MeOD) δ ppm 8.16(dd, J=13.89, 2.29 Hz, 1H) 8.03 (s, 1H) 7.38-7.47 (m, 3H) 7.34 (t,J=8.70 Hz, 1H) 7.05-7.14 (m, 2H) 5.85 (d, J=1.83 Hz, 1H) 5.16 (br. s.,1H) 5.04 (br. s., 1H) 3.07 (s, 3H) 2.39 (s, 3H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 82A and 82B as free amines, which had identicalspectral data.

Example 83N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine,2 TFA

Diasteriomeric Mixture

2-chloro-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation Mg) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine,2 TFA as a mixture of two diasteriomers (Example 83). LC-MS(M+H)⁺=525.1. ¹H NMR (500 MHz, MeOD) δ ppm 7.83 (br. s., 1H) 7.57 (br.s., 1H) 7.43-7.52 (m, 2H) 7.32-7.41 (m, 2H) 7.22-7.29 (m, 1H) 7.10-7.22(m, 2H) 6.00-6.11 (m, 1H) 5.38-5.50 (m, 3H) 4.10 (br. s., 2H) 3.90 (br.s., 2H) 2.31-2.51 (m, 2H).

The mixture of two diasteriomers was separated by chiral chromatographyto afford two diasteriomers Example 83A and 83B as free amines

Example 83A: LC-MS (M+H)⁺=525.2. ¹H NMR (500 MHz, MeOD) δ ppm 7.80 (d,J=1.83 Hz, 1H) 7.69 (d, J=1.53 Hz, 1H) 7.43 (dd, J=8.70, 5.34 Hz, 2H)7.23 (d, J=1.22 Hz, 1H) 7.04-7.20 (m, 4H) 5.77 (br. s., 1H) 5.50-5.59(m, 1H) 5.27-5.39 (m, 2H) 4.00 (d, J=11.90 Hz, 1H) 3.82-3.96 (m, 2H)3.63-3.82 (m, 4H) 2.26-2.42 (m, 2H).

Example 83B: LC-MS (M+H)⁺=525.2. ¹H NMR (500 MHz, MeOD) δ ppm 7.81 (d,J=1.83 Hz, 1H) 7.69 (d, J=1.53 Hz, 1H) 7.39-7.47 (m, 2H) 7.24 (d, J=1.53Hz, 1H) 7.16-7.21 (m, 1H) 7.05-7.16 (m, 3H) 5.80 (t, J=2.59 Hz, 1H) 5.51(dd, J=10.38, 3.05 Hz, 1H) 5.36-5.46 (m, 2H) 3.91 (m, 2H) 3.66-3.86 (m,5H) 2.23-2.42 (m, 2H).

Example 84N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine,2 TFA

2-chloro-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine(Preparation Mh) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine,2 TFA (Example 84). LC-MS (M+H)⁺=551.2. ¹H NMR (400 MHz, MeOD) δ ppm7.80 (d, J=1.51 Hz, 1H) 7.55 (d, J=2.27 Hz, 1H) 7.35-7.46 (m, 2H)7.23-7.33 (m, 2H) 7.01-7.18 (m, 3H) 5.91 (t, J=2.77 Hz, 1H) 5.42 (dd,J=10.45, 3.40 Hz, 1H) 5.28 (dd, J=10.32, 2.27 Hz, 1H) 4.16 (br. s., 2H)3.60-3.78 (m, 5H) 2.81 (ddd, J=13.41, 10.51, 3.53 Hz, 2H) 1.21 (d,J=6.04 Hz, 6H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 84A and 84B as free amines LC-MS (M+H)⁺=551.2. ¹HNMR (500 MHz, MeOD) δ ppm 7.77 (d, J=2.14 Hz, 1H) 7.69 (d, J=1.53 Hz,1H) 7.35-7.50 (m, 2H) 7.24 (d, J=1.53 Hz, 1H) 7.18 (d, J=8.55 Hz, 1H)7.10 (t, J=8.70 Hz, 2H) 7.05 (dd, J=8.55, 2.14 Hz, 1H) 5.80 (d, J=2.44Hz, 1H) 5.42 (dd, J=10.38, 3.05 Hz, 1H) 5.28 (dd, J=10.38, 1.83 Hz, 1H)4.16 (br. s., 2H) 3.61-3.76 (m, 5H) 2.60-2.80 (m, 2H) 1.23 (d, J=6.41Hz, 6H).

Example 85N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.168 g, 0.75 mmol), Preparation Na (0.23g, 0.834 mmol), Na₂CO₃ (0.176 g, 1.6 mmol) and xantphos (0.482 g, 0.834mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.38 g, 0.417 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through celite bed and washed with ethyl acetate. The filtratewas evaporated under reduced pressure and the residue was diluted withwater. The aqueous solution was extracted with ethyl acetate (75 mL×2).The combined organic layer was washed with brine solution (50 mL), driedover anhydrous Na₂SO₄ and evaporated under reduced pressure to get crudecompound. The crude compound was purified by prep-HPLC (aqueous 0.1%ammonium acetate in acetonitrile) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine(0.140 g, 36.2%) as off-white solid. LC-MS (M+H)⁺=463.2. ¹H NMR (400MHz, DMSO-d6): δ ppm 9.06 (1H, s), 7.96 (1H, s), 7.72 (1H, s), 7.4 (1H,s), 7.36-7.30 (5H, m), 7.13 (2H, m), 6.94 (1H, m), 5.43 (1H, s), 3.95(1H, m), 3.81 (1H, s), 3.53 (3H, s), 2.97 (3H, d, J=4.4 Hz), 2.52 (1H,m), 2.45 (1H, m).

Example 86N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine

A solution of Preparation B (0.119 g, 0.62 mmol), Preparation Na (0.19g, 0.68 mmol), Na₂CO₃ (0.146 g, 1.37 mmol) and xantphos (0.399 g, 0.689mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.315 g, 0.344 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (75 mL×2). The combined organic layer was washed withbrine solution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to giveN²-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine(0.120 g, 30%) as off-white solid. LC-MS (M+H)⁺=432.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.33 (1H, s), 8.68 (1H, s), 8.03 (1H, m), 7.42-7.24 (7H,m), 6.98 (1H, bs), 5.44 (1H, s), 4.06 (1H, m), 3.84 (1H, m), 2.95 (3H,d, J=4.4 Hz), 2.59 (1H, m), 2.44 (1H, m), 2.34 (3H, s).

Example 87N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine

A solution of Preparation C (0.119 g, 0.62 mmol), Preparation Na (0.19g, 0.68 mmol), Na₂CO₃ (0.146 g, 1.37 mmol) and xantphos (0.399 g, 0.689mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.315 g, 0.344 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (75 mL×2). The combined organic layer was washed withbrine solution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to giveN2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine(0.130 g, 44%) as off-white solid. LC-MS (M+H)⁺=432.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.38 (1H, s), 8.04 (1H, s), 8.01 (1H, s), 7.44 (1H, m),7.34-7.27 (6H, m), 6.99 (1H, bs), 5.43 (1H, s), 4.06 (1H, m), 3.83 (1H,m), 2.95 (3H, d, J=4.4.0 Hz), 2.51 (1H, m), 2.44 (1H, m), 2.27 (3H, s).

Example 88N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.09 g, 0.38 mmol), Preparation Oa (0.15 g,0.48 mmol), Na₂CO₃ (0.103 g, 0.97 mmol) and xantphos (0.282 g, 0.41mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.270 g, 0.24 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (75 mL×2). The combined organic layer was washed withbrine solution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (60-120 mesh) using 35% ethyl acetate inpet-ether as mobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine(0.90 g, 55%) as off-white solid. LC-MS (M+H)⁺=495.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.06 (1H, s), 7.88 (1H, s), 7.73 (1H, m), 7.42 (1H, m),7.33-7.44 (2H, m), 7.14-7.15 (4H, m), 6.92 (1H, m), 5.44 (1H, s), 3.96(1H, m), 3.82 (1H, m), 3.57 (3H, s), 3.50 (2H, m), 2.45 (2H, m), 1.21(3H, m).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 88A and 88B, which had identical spectral data.

Example 89N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.029 g, 0.10 mmol), Preparation Ob (0.050g, 0.14 mmol), Na₂CO₃ (0.030 g, 0.28 mmol) and xantphos (0.080 g, 0.14mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.078 g, 0.07 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (75 mL×2). The combined organic layer was washed withbrine solution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (60-120 mesh) using 35% ethyl acetate inpet-ether as mobile phase to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine(0.020 g, 30%) as off-white solid. LC-MS (M+H)⁺=509.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.12 (1H, s), 7.75-7.81 (2H, m), 7.38-7.44 (3H, m),7.15-7.24 (4H, m), 5.51 (1H, s), 4.03 (1H, m), 3.49-3.67 (5H, m), 3.09(3H, m), 3.01-3.06 (1H, m), 2.51-2.59 (2H, m), 1.22 (3H, t, J=7.2 Hz).

Example 90AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine

A solution of Preparation A (0.063 g, 0.20 mmol), Preparation Oc1 (0.110g, 0.3 mmol), Na₂CO₃ (0.066 g, 0.6 mmol) and xantphos (0.181 g, 0.3mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0172 g, 0.10 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (75 mL×2). The combined organic layer was washed withbrine solution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (60-120 mesh) using 35% ethyl acetate inpet-ether as mobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine(0.050 g, 60%) as off-white solid. LC-MS (M+H)⁺=539.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.12 (1H, s), 7.75 (2H, m), 7.39-7.44 (3H, m), 7.15-7.22(4H, m), 5.50 (1H, s), 5.38 (1H, m), 3.82-4.09 (6H, m), 3.68 (3H, s),2.98 (2H, m), 2.50-2.43 (2H, m).

Example 90BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine

A solution of Preparation A (0.063 g, 0.20 mmol), Preparation Oc2 (0.110g, 0.3 mmol), Na₂CO₃ (0.066 g, 0.6 mmol) and xantphos (0.181 g, 0.3mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0172 g, 0.10 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (75 mL×2). The combined organic layer was washed withbrine solution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (60-120 mesh) using 35% ethyl acetate inpet-ether as mobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine(0.070 g, 63%) as off-white solid. LC-MS (M+H)⁺=539.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.16 (1H, s), 7.81 (1H, s), 7.74 (1H, s), 7.73 (1H, s),7.42 (2H, m), 7.17-7.11 (4H, m), 5.54 (1H, s), 5.43 (1H, m), 4.12-3.57(6H, m), 3.34 (3H, s), 2.97 (2H, m), 2.50-2.43 (2H, m).

Example 91AN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine

A solution of Preparation A (0.063 g, 0.20 mmol), Preparation Od1 (0.110g, 0.3 mmol), Na₂CO₃ (0.066 g, 0.6 mmol) and xantphos (0.181 g, 0.3mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0172 g, 0.10 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (75 mL×2). The combined organic layer was washed withbrine solution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (60-120 mesh) using 35% ethyl acetate inpet-ether as mobile phase toN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine(0.040 g, 40%) as off-white solid. LC-MS (M+H)⁺=539.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.25 (1H, s), 7.77 (1H, s), 7.77 (1H, s), 7.45 (3H, m),7.21 (4H, m), 5.53 (1H, s), 5.43 (1H, m), 4.12-3.57 (5H, m), 3.34 (3H,s), 3.33 (1H, m), 3.20 (1H, m), 2.73 (1H, m), 2.31-2.06 (2H, m).

Example 91BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-448)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine

A solution of Preparation A (0.063 g, 0.20 mmol), Preparation Od2 (0.110g, 0.3 mmol), Na₂CO₃ (0.066 g, 0.6 mmol) and xantphos (0.181 g, 0.3mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0172 g, 0.10 mmol) was added to the reactionmixture and the resulting solution was purged for another 1 h. Thereaction mass was heated at 110° C. for 24 h. The reaction mass wasfiltered through a bed of diatomaceous earth (Celite®) and washed withethyl acetate. The filtrate was evaporated under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (75 mL×2). The combined organic layer was washed withbrine solution (50 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby column chromatography (60-120 mesh) using 35% ethyl acetate inpet-ether as mobile phase to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine(0.039 g, 39%) as off-white solid. LC-MS (M+H)⁺=539.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.15 (1H, s), 7.81 (1H, s), 7.74 (1H, s), 7.43 (1H, s),7.37 (2H, m), 7.19 (4H, m), 5.54 (1H, s), 5.43 (1H, m), 4.13-3.69 (6H,m), 3.33 (3H, s), 2.96 (2H, m), 2.24-1.91 (2H, m).

Example 92N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-7-(4-chlorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(98 mg, 0.318 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (71.1 mg, 0.318 mmol) inacetic acid (1.000 mL) and THF (1 mL). The reaction mixture was heatedat 75° C. overnight. Partial conversion to the desired product wasobserved. The reaction was further heated at 120° C. for 6 h. The crudereaction mixture was purified by preparative HPLC. The appropriatefractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (17.2 mg, 0.028 mmol, 8.70% yield). LC-MS (M+H)⁺=495.1. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.80 (1H, s), 7.61-7.72 (1H, m), 7.34-7.42 (2H,m), 7.27-7.33 (2H, m), 7.21 (2H, d, J=8.5 Hz), 7.16 (1H, d, J=9.2 Hz),7.06 (1H, d, J=1.5 Hz), 4.30-4.41 (1H, m), 3.82 (6H, s), 3.48 (1H, br.s.), 3.31-3.39 (2H, m), 3.18-3.27 (1H, m), 2.58-2.80 (2H, m), 2.14-2.29(1H, m).

Example 93N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

2-Chloro-7-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(70 mg, 0.197 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (52.7 mg, 0.236 mmol) inacetic acid (1 mL) and THF (1.000 mL). The reaction mixture was heatedat 120° C. in a microwave for 6 h. The crude reaction mixture waspurified by preparative HPLC. The appropriate fractions were evaporatedto affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA salt (8.7 mg, 0.013 mmol, 6.46% yield). LC-MS (M+H)⁺=543.1. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.85-11.99 (1H, m), 7.93 (1H, s), 7.38-7.45 (1H,m), 7.31 (2H, d, J=8.2 Hz), 7.19 (3H, t, J=8.2 Hz), 7.10 (1H, d, J=1.5Hz), 4.37-4.47 (1H, m), 3.85 (3H, s), 3.45-3.51 (1H, m), 3.07-3.18 (2H,m), 2.94-3.04 (2H, m), 2.67-2.81 (2H, m), 2.19-2.37 (2H, m).

Example 94N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-7-(4-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(101 mg, 0.343 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (77 mg, 0.343 mmol) inacetic acid (2 mL) and THF (2 mL). The reaction mixture was heated at80° C. overnight. Partial conversion to the desired product wasobserved. The reaction was further heated at 120° C. for 6 h. The crudereaction mixture was purified by preparative HPLC. The appropriatefractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (35.5 mg, 0.059 mmol, 17.19% yield). LC-MS (M+H)⁺=481.3. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.08 (1H, s), 8.33 (1H, s), 7.48 (2H, d, J=2.1Hz), 7.30 (2H, d, J=8.2 Hz), 7.20 (1H, d, J=1.5 Hz), 7.13 (2H, d, J=8.5Hz), 5.83-5.93 (1H, m), 4.38-4.48 (1H, m), 3.97 (1H, s), 3.86 (3H, s),3.22 (3H, d, J=4.9 Hz), 2.85-2.95 (1H, m), 2.77 (2H, dd, J=8.7, 5.3 Hz),2.20-2.32 (1H, m).

Example 94A & 94B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(37 mg, 0.077 mmol from Example 94) was purified using chiral SFC toafford 10.5 mg of peak A (Example 94A) and 13.6 mg of peak B (Example94B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 35% methanol (0.1%diethylamine) in CO₂, 35° C., flow rate 2.0 mL/min for 20 min,absorbance 268 nm, injection 5 μL of 2 mg/mL solution in 50:50methanol/chloroform (multiple stacked injections), t_(R) (peak A)=5.3min, t_(R) (peak B) 14.9 min. The absolute stereochemistry of individualenantiomers (Examples 94A and 94B) was not determined LC-MS and ¹H NMRanalytical data for the separated enantiomers was identical to theracemate (Example 94).

Example 95N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-7-(3,4-difluorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(178 mg, 0.575 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (141 mg, 0.632 mmol) inacetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heatedat 80° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (144.1 mg, 0.233 mmol, 40.6% yield). LC-MS (M+H)⁺=497.0. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.53-11.67 (1H, m), 8.96 (1H, br s), 7.85-7.96(1H, m), 7.38 (1H, s), 7.18 (1H, d, J=8.2 Hz), 7.00-7.16 (4H, m), 4.34(1H, dd, J=9.6, 4.4 Hz), 3.83 (3H, s), 3.30-3.57 (6H, m), 3.25-3.29 (1H,m), 3.19-3.26 (1H, m), 2.61-2.72 (1H, m), 2.14-2.25 (1H, m).

Example 95A & 95B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(139 mg, 0.28 mmol from Example 95) was purified using chiral SFC toafford 47.6 mg of peak A (Example 95A) and 47.3 mg of peak B (Example95B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 35% methanol (0.1%diethylamine) in CO₂, 35° C., flow rate 2.0 mL/min for 8 min, absorbance268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stackedinjections), t_(R) (peak A)=4.6 min, t_(R) (peak B) 6.3 min. Theabsolute stereochemistry of individual enantiomers (Examples 95A and95B) was not determined LC-MS and ¹H NMR analytical data for theseparated enantiomers was identical to the racemate (Example 95).

Example 96N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-7-(3,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(154 mg, 0.521 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (175 mg, 0.781 mmol) inacetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heatedat 120° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (22.3 mg, 0.034 mmol, 6.46% yield). LC-MS (M+H)⁺=483.2. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.84 (1H, s), 7.83-7.89 (1H, m), 7.55 (1H, s),7.41-7.46 (1H, m), 7.17-7.21 (1H, m), 7.10 (2H, s), 6.98-7.05 (2H, m),5.79-5.90 (1H, m), 4.38-4.45 (1H, m), 3.85 (3H, s), 3.20-3.25 (3H, m),2.90-3.00 (1H, m), 2.70-2.81 (2H, m), 2.20-2.32 (1H, m).

Example 96A & 96B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(1.4 g, 2.345 mmol from Example 96) was purified using chiral SFC toafford 475 mg of peak A (Example 96A) and 435 mg of peak B (Example96B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 25% methanol (0.1%diethylamine) in CO₂, 35° C., flow rate mL/min for 14 min, absorbance268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stackedinjections), t_(R) (peak A)=6.1 min, t_(R) (peak B) 9.2 min. Theabsolute stereochemistry of individual enantiomers (Examples 96A and96B) was not determined LC-MS and ¹H NMR analytical data for theseparated enantiomers was identical to the racemate (Example 96).

Example 97N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-N-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(220 mg, 0.640 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (215 mg, 0.960 mmol) inacetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heatedat 80° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(92 mg, 0.172 mmol, 26.8% yield). LC-MS (M+H)⁺=531.2. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.93 (1H, s), 7.66 (1H, br s), 7.50 (1H, s), 7.10-7.23 (4H,m), 7.02 (2H, d, J=15.3 Hz), 6.83 (1H, d, J=8.2 Hz), 4.70-4.83 (1H, m),4.13-4.28 (1H, m), 3.12 (3H, d, J=4.9 Hz), 2.74 (1H, br. s.), 2.65 (2H,d, J=8.2 Hz), 1.97-2.08 (1H, m), 1.25 (3H, s).

Example 97A & 97B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(86 mg, 0.162 mmol from Example 97) was purified using chiral SFC toafford 36.6 mg of peak A (Example 97A) and 31.5 mg of peak B (Example97B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1%diethylamine) in CO₂, 35° C., flow rate 2.0 mL/min for 12 min,absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol(multiple stacked injections), t_(R) (peak A)=3.4 min, t_(R) (peak B)7.5 min. The absolute stereochemistry of individual enantiomers(Examples 97A and 97B) was not determined LC-MS and ¹H NMR analyticaldata for the separated enantiomers was identical to the racemate(Example 97).

Example 98N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-N-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(190 mg, 0.531 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (178 mg, 0.797 mmol) inacetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heatedat 90° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (118 mg, 0.174 mmol, 32.7% yield). LC-MS (M+H)⁺=545.0. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.04 (1H, s), 9.01 (1H, br s), 8.29 (1H, s),7.44 (2H, s), 7.24 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=5.5 Hz), 7.09-7.12(1H, m), 5.93-5.99 (1H, m), 4.43-4.51 (1H, m), 3.86 (3H, s), 3.62-3.74(2H, m), 3.46-3.55 (1H, m), 2.85-2.97 (1H, m), 2.71-2.82 (2H, m), 2.26(1H, m), 1.26-1.41 (3H, m).

Example 98A & 98B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(111 mg, 0.204 mmol from Example 98) was purified using chiral SFC toafford 29.5 mg of peak A (Example 98A) and 37.7 mg of peak B (Example98B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1%diethylamine) in CO₂, 35° C., flow rate 2.0 mL/min for 12 min,absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol(multiple stacked injections), t_(R) (peak A)=3.4 min, t_(R) (peak B)8.2 min. The absolute stereochemistry of individual enantiomers(Examples 98A and 98B) was not determined LC-MS and ¹H NMR analyticaldata for the separated enantiomers was identical to the racemate(Example 98).

Example 99N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

2-Chloro-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(244 mg, 0.601 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (202 mg, 0.902 mmol) inacetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heatedat 110° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA salt (165.2 mg, 0.229 mmol, 38.1% yield). LC-MS (M-FH)⁺=593.3. ¹HNMR (500 MHz, CDCl₃) δ ppm 11.83 (1H, s), 8.00 (1H, s), 7.38-7.43 (1H,m), 7.30-7.33 (1H, m), 7.27-7.28 (1H, m), 7.16-7.22 (3H, m), 7.09-7.12(1H, m), 4.76 (1H, br s), 4.46 (1H, dd, J=9.5, 4.9 Hz), 3.85 (3H, s),3.07-3.17 (2H, m), 2.95-3.04 (2H, m), 2.70-2.81 (2H, m), 2.21-2.34 (2H,m).

Example 99A & 99B(S)—N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amineand(R)—N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

A racemic mixture ofN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(165.2 mg, 0.279 mmol from Example 99) was purified using chiral SFC toafford 16.7 mg of peak A (Example 99A) and 17.0 mg of peak B (Example99B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1%diethylamine) in CO₂, 35° C., flow rate 2.0 mL/min for 20 min,absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol(multiple stacked injections), t_(R) (peak A)=4.9 min, t_(R) (peak B)15.0 min. The absolute stereochemistry of individual enantiomers(Examples 99A and 99B) was not determined LC-MS and ¹H NMR analyticaldata for the separated enantiomers was identical to the racemate(Example 99).

Example 100N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-N,N-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(250 mg, 0.699 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (234 mg, 1.048 mmol) inacetic acid (1 mL) and THF (1 mL). The reaction mixture was heated at110° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (235 mg, 0.342 mmol, 49.0% yield). LC-MS (M+H)⁺=545.3. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.18-11.39 (1H, m), 8.11 (1H, s), 7.40-7.45 (1H,m), 7.30-7.34 (1H, m), 7.28 (1H, s), 7.17-7.23 (3H, m), 7.12-7.15 (1H,m), 4.34-4.44 (1H, m), 3.84 (3H, s), 3.50 (4H, s), 3.33-3.39 (3H, m),3.18-3.27 (1H, m), 2.57-2.78 (1H, m), 2.10-2.39 (1H, m).

Example 100A & 100B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(235 mg, 0.431 mmol from Example 100) was purified using chiral SFC toafford 29.2 mg of peak A (Example 100A) and 29.2 mg of peak B (Example100B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1%diethylamine) in CO₂, 35° C., flow rate 2.0 mL/min for 11 min,absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol(multiple stacked injections), t_(R) (peak A)=3.7 min, t_(R) (peak B)8.4 min. The absolute stereochemistry of individual enantiomers(Examples 100A and 100B) was not determined. LC-MS and ¹H NMR analyticaldata for the separated enantiomers was identical to the racemate(Example 100).

Example 1014-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

4-(Azetidin-1-yl)-2-chloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(238 mg, 0.644 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (216 mg, 0.965 mmol) inacetic acid (2 mL) and THF (2 mL). The reaction mixture was heated at85° C. overnight. The crude reaction mixture was purified by preparativeHPLC. The appropriate fractions were evaporated to afford4-(azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA salt (99.3 mg, 0.148 mmol, 22.99% yield). LC-MS (M+H)⁺=557.2. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.78 (1H, s), 7.51-7.65 (2H, m), 7.33-7.40 (1H,m), 7.26 (2H, d, J=3.1 Hz), 7.17 (3H, s), 7.04 (1H, s), 4.58-4.71 (2H,m), 4.27-4.46 (3H, m), 3.82 (3H, s), 2.91-3.17 (2H, m), 2.61-2.74 (1H,m), 2.50-2.60 (2H, m), 2.14-2.30 (1H, m).

Example 101A & 101B(S)-4-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amineand(R)-4-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

A racemic mixture of4-(azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(92 mg, 0.165 mmol from Example 101) was purified using chiral SFC toafford 37.6 mg of peak A (Example 101A) and 39.1 mg of peak B (Example101B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1%diethylamine) in CO₂, 35° C., flow rate 2.0 mL/min for 18 min,absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol(multiple stacked injections), t_(R) (peak A)=4.7 min, t_(R) (peak B)13.6 min. The absolute stereochemistry of individual enantiomers(Examples 101A and 101B) was not determined LC-MS and ¹H NMR analyticaldata for the separated enantiomers was identical to the racemate(Example 101).

Example 102N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,5-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-7-(3,5-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(60 mg, 0.203 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (68.1 mg, 0.304 mmol) inacetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heatedat 80° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,5-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (33.6 mg, 0.056 mmol, 27.5% yield). LC-MS (M+H)⁺=483.0. ¹H NMR(500 MHz, MeOD) δ ppm 7.79 (1H, s), 7.70 (1H, s), 7.29-7.45 (2H, m),7.22 (1H, d, J=8.5 Hz), 6.86-7.03 (3H, m), 4.27-4.60 (1H, m), 3.89 (3H,s), 3.24-3.48 (5H, m), 3.17 (1H, s), 2.88-3.01 (1H, m), 2.67-2.87 (1H,m), 2.03-2.32 (1H, m).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 102A and 102B as free amines, which had identicalspectral data.

Example 103N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(100 mg, 0.319 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (107 mg, 0.478 mmol) inacetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heatedat 80° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (36.3 mg, 0.057 mmol, 17.78% yield). LC-MS (M+H)⁺=501.0. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.88-11.96 (1H, m), 7.95-8.01 (1H, m), 7.44-7.62(2H, m), 7.09-7.19 (1H, m), 6.86-6.95 (2H, m), 5.55-5.66 (1H, m),5.26-5.39 (1H, m), 4.36-4.54 (1H, m), 3.90 (3H, s), 3.22-3.33 (3H, m),2.72-2.87 (3H, m), 2.18-2.38 (1H, m).

Example 103A & 103B(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(59.8 mg, 0.119 mmol from Example 103) was purified using chiral SFC toafford 19.5 mg of peak A (Example 103A) and 34.8 mg of peak B (Example103B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 20% methanol (0.1%diethylamine) in CO₂, 35° C., flow rate 2.0 mL/min for 16 min,absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol(multiple stacked injections), t_(R) (peak A)=9.7 min, t_(R) (peak B)11.9 min. The absolute stereochemistry of individual enantiomers(Examples 103A and 103B) was not determined LC-MS and ¹H NMR analyticaldata for the separated enantiomers was identical to the racemate(Example 103).

Example 104N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(65.3 mg, 0.208 mmol) was added to a solution of3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (40 mg, 0.208 mmol)in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture washeated at 80° C. overnight. Partial formation of the desired product wasobserved. The reaction mixture was heated at 130° C. for 6 h. The crudereaction mixture was purified by preparative HPLC. The appropriatefractions were evaporated to affordN²-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (5.3 mg, 8.99 μmol, 4.32% yield). LC-MS (M+H)⁺=470.0. ¹H NMR(500 MHz, CDCl₃) δ ppm 12.17 (1H, s), 8.75 (1H, d, J=1.8 Hz), 8.05 (1H,dd, J=13.7, 2.1 Hz), 7.80 (1H, t, J=8.7 Hz), 7.44-7.65 (1H, m),6.74-6.99 (2H, m), 5.33-5.66 (1H, m), 4.34-4.67 (1H, m), 3.42-3.74 (2H,m), 3.29 (3H, d, J=4.9 Hz), 2.70-2.99 (2H, m), 2.57 (2H, s), 2.14-2.38(1H, m).

Example 105N²-(6-(4-Chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(100 mg, 0.319 mmol) was added to a solution of6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (107 mg, 0.478mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture washeated at 80° C. overnight. Partial formation of the desired product wasobserved. The reaction mixture was heated at 130° C. for 6 h. The crudereaction mixture was purified by preparative HPLC. The appropriatefractions were evaporated to affordN²-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (12.9 mg, 0.021 mmol, 6.50% yield). LC-MS (M+H)⁺=502.2. ¹H NMR(500 MHz, CDCl₃) δ ppm 12.33 (1H, s), 8.75 (1H, s), 8.56 (1H, s),7.61-7.89 (2H, m), 6.85-7.00 (2H, m), 5.62-5.79 (1H, m), 4.36-4.49 (1H,m), 4.02 (3H, s), 3.29 (3H, d, J=4.9 Hz), 2.88-2.98 (1H, m), 2.76-2.85(2H, m), 2.21-2.38 (1H, m).

Example 106N²-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(80 mg, 0.255 mmol) was added to a solution of4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (86 mg, 0.383 mmol)in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture washeated at 80° C. overnight. Partial formation of the desired product wasobserved. The reaction mixture was heated at 120° C. for 4 h. The crudereaction mixture was purified by preparative HPLC. The appropriatefractions were evaporated to affordN²-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (15.5 mg, 0.025 mmol, 9.77% yield). LC-MS (M+H)⁺=502.0. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.88-12.12 (1H, m), 8.63 (1H, s), 7.68-7.81 (1H,m), 7.60 (1H, s), 7.47 (1H, s), 6.92 (1H, t, J=7.2 Hz), 3.94-3.99 (1H,m), 3.52 (8H, s), 3.22-3.29 (1H, m), 2.87-3.01 (1H, m), 2.74-2.85 (1H,m), 2.22-2.38 (1H, m).

Example 107N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

2-Chloro-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(105 mg, 0.269 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (90 mg, 0.404 mmol) inacetic acid (1 mL) and THF (1.000 mL). The reaction mixture was heatedat 80° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA salt (54.1 mg, 0.074 mmol, 27.3% yield). LC-MS (M+H)⁺=577.1. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.70 (1H, s), 8.08-8.24 (1H, m), 7.40-7.57 (1H,m), 7.18 (1H, s), 6.88-7.01 (2H, m), 4.37-4.45 (1H, m), 4.24-4.35 (2H,m), 4.03-4.22 (2H, m), 3.98-4.03 (1H, m), 3.89 (3H, s), 3.50-3.58 (1H,m), 3.15-3.42 (2H, m), 2.48-2.89 (3H, m), 2.18-2.34 (1H, m).

Example 107A & 107B(S)—N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amineand(R)—N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

A racemic mixture ofN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(48 mg, 0.083 mmol from Example 107) was purified using chiral SFC toafford 19.8 mg of peak A (Example 107A) and 17.2 mg of peak B (Example107B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 25% methanol (0.1%diethylamine) in CO₂, 35° C., flow rate 2.0 mL/min for 30 min,absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol(multiple stacked injections), t_(R) (peak A)=17.4 min, t_(R) (peak B)21.2 min. The absolute stereochemistry of individual enantiomers(Examples 107A and 107B) was not determined LC-MS and ¹H NMR analyticaldata for the separated enantiomers was identical to the racemate(Example 107).

Example 108N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

2-Chloro-4-(3,3-difluoroazetidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(105 mg, 0.279 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (94 mg, 0.419 mmol) inacetic acid (1 mL) and THF (1.000 mL). The reaction mixture was heatedat 80° C. overnight. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA salt (31.4 mg, 0.044 mmol, 15.60% yield). LC-MS (M+H)⁺=563.1. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.87 (1H, s), 8.09 (1H, s), 7.45 (1H, dd, J=8.5,1.5 Hz), 7.36 (1H, s), 7.29 (2H, s), 7.25 (1H, d, J=8.5 Hz), 7.16 (1H,s), 6.91 (2H, t, J=6.9 Hz), 4.40 (1H, dd, J=9.2, 4.9 Hz), 4.00 (1H, s),3.89 (3H, s), 3.53 (1H, s), 3.08-3.19 (1H, m), 2.97-3.06 (1H, m),2.72-2.84 (1H, m), 2.26 (1H, td, J=9.2, 4.3 Hz).

Example 109N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(2,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A solution of2-chloro-7-(2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(184.6 mg, 0.624 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (140 mg, 0.624 mmol) inTHF (1095 μL) and acetic acid (1095 μL) was heated 80° C. in a cappedvial overnight. The solvent was evaporated in vacuum and the residue waspartitioned between aqueous sodium bicarbonate solution anddichloromethane. The organic layer was separated and the aqueous layerwas extracted with dichloromethane. the combined organic extracts weredried over anhydrous magnesium sulfate and filtered. The solvent wasremoved in vacuum and the residue was purified by column chromatographyon silica gel to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(2,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(179.6 mg, 0.372 mmol, 59.6% yield) as brown solid. LC-MS (M+H)⁺=483.1.¹H NMR (500 MHz, CDCl₃) δ ppm 7.97 (1H, d, J=2.1 Hz), 7.49 (1H, d, J=1.5Hz), 7.01-7.10 (2H, m), 7.00 (1H, d, J=1.5 Hz), 6.73-6.84 (3H, m), 4.44(1H, s), 3.61 (3H, s), 3.11 (3H, d, J=4.9 Hz), 2.59-2.77 (2H, m),1.95-2.05 (2H, m).

Examples 109A and 109B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(2,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(2,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(180 mg, 0.206 mmol from Example 109) was purified using chiralsupercritical fluid chromatography (SFC) to afford 28.4 mg of peak A(Example 109A) and 27.4 mg of peak B (Example 109B). SFC Method:Chiralpak OJ-H (21×250 mm, 5 μM), 35% methanol (0.1% diethylamine) inCO₂, 35° C., flow rate 45 mL/min for 10 min, absorbance 268 nm,injection 0.75 mL of 20 mg/mL solution in methanol (multiple stackedinjections), t_(R) (peak A)=3.6 min, t_(R) (peak B) 7.2 min. Theabsolute stereochemistry of individual enantiomers (Examples 109A and109B) was not determined LC-MS and ¹H NMR analytical data for theseparated enantiomers was identical to the racemate (Example 109).

Example 110N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The method of Example 74 was used to combine Preparation Va and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to affordN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 110). LC-MS (M+H)⁺=475.2. ¹H NMR (500 MHz, METHANOL-d4) δ ppm8.03 (1H, d, J=2.14 Hz), 7.65 (1H, s), 7.22-7.30 (4H, m), 7.20 (1H, s),7.10-7.16 (2H, m), 7.02 (1H, dd, J=8.55, 2.14 Hz), 3.66 (3H, s), 3.56(2H, q, J=7.32 Hz), 2.56-2.69 (2H, m), 2.30-2.38 (1H, m), 2.14-2.22 (1H,m), 1.25 (3H, d, J=7.20 Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 110A and 110B, which had identical spectral data.

Example 111N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-7-allyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The method of Example 74 was used to combine Preparation Wa and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to affordN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-7-allyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 111). LC-MS (M+H)⁺=501.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 11.66(1H, br. s.), 7.45-7.54 (2H, m), 7.32-7.39 (5H, m), 7.25-7.30 (3H, m),5.57-5.68 (1H, m, J=16.94, 9.92, 7.17, 7.17 Hz), 5.42 (1H, br. s.), 5.22(1H, d, J=16.17 Hz), 5.12 (1H, d, J=10.07 Hz), 3.85 (3H, s), 3.63-3.70(2H, m), 3.05-3.12 (2H, m), 2.64-2.80 (2H, m), 2.51-2.63 (2H, m), 1.35(3H, t, J=7.17 Hz).

Example 112N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(3,5-difluorophenyl)-N4-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA

The mixture of2-chloro-8-(3,5-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Xa) (87 mg, 0.267 mmol),4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (71.7 mg,0.321 mmol), tris(dibenzylideneacetone)dipalladium(0) (12.23 mg, 0.013mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (15.45mg, 0.027 mmol) and sodium carbonate (42.5 mg, 0.401 mmol) in Dioxane(1272 μL)/Water (254 μL) was heated at 110° C. overnight. The reactionmixture was diluted with water and extracted with EtOAc. The combinedorganic layers were washed with brine and concentrated in vacuum. Thecrude product was purified by Prep-HPLC (Solvent A=10% Acetonitrile-90%H2O-0.1% TFA, Solvent B=90% Acetonitrile-10% H2O-0.1% TFA. Column.PHENOMENEX LUNA 21×100 mm, 10uC18, Flow rate: 25 ml/min, 30-100% B, 20min) to obtainN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(3,5-difluorophenyl)-N4-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (Example 112) (123 mg, 0.177 mmol, 66.1% yield). LC-MS (M+H)⁺=513.2.¹H NMR (500 MHz, CDCl₃) δ ppm 11.71 (s, 1H) 8.04 (s, 1H) 7.49 (d, J=2.14Hz, 1H) 7.43 (dd, J=8.55, 2.14 Hz, 1H) 7.23 (d, J=8.55 Hz, 1H) 7.17 (d,J=1.53 Hz, 1H) 7.00 (d, J=5.80 Hz, 2H) 6.70-6.84 (m, 1H) 6.09 (t, J=5.19Hz, 1H) 4.73 (d, J=14.34 Hz, 1H) 4.54 (d, J=14.34 Hz, 1H) 3.95-4.15 (m,3H) 3.88 (s, 3H) 3.61-3.78 (m, 2H) 1.37 (t, J=7.17 Hz, 3H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 112A and 112B as free amines LC-MS (M+H)⁺=513.2. ¹HNMR (500 MHz, MeOD) δ ppm 7.84 (d, J=2.14 Hz, 1H) 7.67 (d, J=1.53 Hz,1H) 7.21 (d, J=1.53 Hz, 1H) 7.13 (d, J=8.55 Hz, 1H) 6.98-7.08 (m, 1H)6.89 (d, J=2.14 Hz, 1H) 6.74-6.85 (m, 1H) 4.65 (d, J=14.34 Hz, 1H)4.46-4.59 (m, 1H) 4.11 (dd, J=11.44, 4.43 Hz, 1H) 3.96 (dd, J=11.44,4.12 Hz, 1H) 3.88 (d, J=3.97 Hz, 1H) 3.66 (s, 3H) 3.58 (q, J=7.32 Hz,2H) 1.27 (t, J=7.17 Hz, 3H).

Example 113N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(3,4-difluorophenyl)-N4-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA

2-chloro-8-(3,4-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Ya) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(3,4-difluorophenyl)-N4-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (Example 113). LC-MS (M+H)⁺=513.5. ¹H NMR (500 MHz, MeOD) δ ppm 7.84(d, J=1.22 Hz, 1H) 7.58 (d, J=2.14 Hz, 1H) 7.32-7.49 (m, 3H) 7.12-7.32(m, 3H) 4.71 (d, J=14.95 Hz, 1H) 4.55 (d, J=14.65 Hz, 1H) 4.14 (dd,J=11.60, 4.27 Hz, 1H) 4.06 (br. s., 1H) 3.92-4.02 (m, 1H) 3.89 (s, 3H)3.68-3.70 (m, 2H) 1.32 (t, J=7.17 Hz, 3H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 113A and 113B as free amines LC-MS (M+H)⁺=513.3. ¹HNMR (500 MHz, MeOD) δ ppm 7.83 (d, J=2.14 Hz, 1H) 7.67 (s, 1H) 7.09-7.25(m, 4 H) 6.96-7.09 (m, 2H) 4.59-4.69 (m, 1H) 4.47-4.57 (m, 1H) 4.10 (dd,J=11.29, 4.27 Hz, 1H) 3.92 (dd, J=11.60, 4.27 Hz, 1H) 3.86 (d, J=3.36Hz, 1H) 3.62-3.68 (m, 3H) 3.57 (q, J=7.32 Hz, 2H) 1.22-1.34 (m, 3H).

Example 114N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine,TFA

2-chloro-4-(3,3-difluoroazetidin-1-yl)-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(Preparation Yb) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine,TFA (Example 114). LC-MS (M+H)⁺=561.5. ¹H NMR (500 MHz, CDCl₃) δ ppm12.12 (br. s., 1H) 7.80 (s, 1H) 7.38 (dd, J=8.55, 1.83 Hz, 1H) 7.20-7.31(m, 4H) 7.09-7.18 (m, 2H) 4.69-4.89 (m, 6H) 4.06 (m, 3H) 3.87 (s, 3H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 114A and 114B as free amines LC-MS (M+H)⁺=561.3. ¹HNMR (500 MHz, MeOD) δ ppm 7.74 (s, 1H) 7.66 (s, 1H) 7.10-7.24 (m, 4H)7.08 (d, J=1.53 Hz, 1H) 7.02 (d, J=8.55 Hz, 1H) 4.76-4.84 (m, 1H) 4.68(d, J=14.04 Hz, 1H) 4.59 (t, J=12.21 Hz, 4H) 4.14 (dd, J=11.29, 3.66 Hz,1H) 3.98 (br. s., 1H) 3.86-3.94 (m, 1H) 3.59 (s, 3H).

Example 115N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(3,4-difluorophenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA

2-chloro-8-(3,4-difluorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Yc) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(3,4-difluorophenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (Example 115). LC-MS (M+H)⁺=499.5. ¹H NMR (500 MHz, MeOD) δ ppm 7.86(d, J=1.53 Hz, 1H) 7.66 (d, J=2.14 Hz, 1H) 7.26-7.41 (m, 4H) 7.17-7.25(m, 2H) 4.70 (d, J=14.65 Hz, 1H) 4.54 (dd, J=14.95, 1.53 Hz, 1H) 4.15(dd, J=11.60, 4.27 Hz, 1H) 4.07 (br. s., 1H) 3.96 (dd, J=11.60, 3.36 Hz,1H) 3.89 (s, 3H) 3.16 (s, 3H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 115A and 115B as free amines LC-MS (M+H)⁺=499.3. ¹HNMR (500 MHz, MeOD) δ ppm 7.90 (d, J=2.14 Hz, 1H) 7.67 (d, J=1.53 Hz,1H) 7.12-7.25 (m, 4H) 7.07 (d, J=2.14 Hz, 1H) 6.98-7.05 (m, 1H) 4.63 (d,J=14.34 Hz, 1H) 4.45-4.57 (m, 1H) 4.11 (dd, J=11.44, 4.43 Hz, 1H) 3.93(dd, J=11.44, 4.43 Hz, 1H) 3.87 (d, J=3.97 Hz, 1H) 3.61-3.70 (m, 3H)3.00-3.08 (m, 3H).

Example 1168-(3,4-difluorophenyl)-N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA

2-chloro-8-(3,4-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Ya) was reacted as described in Example 112 with3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation C) togive8-(3,4-difluorophenyl)-N⁴-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (Example 116).

LC-MS (M+H)⁺=482.3 ¹H NMR (500 MHz, MeOD) δ ppm 8.13 (s, 1H) 7.95 (dd,J=12.36, 1.98 Hz, 1H) 7.47-7.62 (m, 2H) 7.30-7.42 (m, 1H) 7.23-7.30 (m,1H) 7.21 (br. s., 1H) 4.72 (d, J=14.95 Hz, 1H) 4.55 (d, J=14.95 Hz, 1H)4.14 (dd, J=11.44, 4.12 Hz, 1H) 4.07 (br. s., 1H) 3.91-4.01 (m, 1H)3.58-3.75 (m, 2H) 2.44 (s, 3H) 1.26-1.43 (m, 3H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 116A and 116B as free amines LC-MS (M+H)⁺=482.3. ¹HNMR ¹H NMR (500 MHz, MeOD) δ ppm 8.05 (d, J=2.14 Hz, 1H) 8.03 (s, 1H)7.27-7.34 (m, 2H) 7.17-7.25 (m, 2H) 7.12 (d, J=1.83 Hz, 1H) 4.61-4.68(m, 1H) 4.56 (t, J=14.19 Hz, 1H) 4.15 (dd, J=11.29, 4.58 Hz, 1H) 4.00(dd, J=11.44, 4.73 Hz, 1H) 3.90 (d, J=4.27 Hz, 1H) 3.58-3.66 (m, 2H)2.38 (s, 3H) 1.19 (t, J=7.02 Hz, 3H).

Example 117N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((R)-1-cyclopropylethyl)-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA

2-chloro-N—((R)-1-cyclopropylethyl)-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Zc) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((R)-1-cyclopropylethyl)-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (Example 117). LC-MS (M+H)⁺=585.4. ¹H NMR (500 MHz, CDCl₃) δ ppm11.95 (s, 1H) 7.68 (d, J=1.53 Hz, 1H) 7.52-7.65 (m, 4H) 7.31-7.43 (m,2H) 7.16-7.22 (m, 1H) 7.10 (d, J=1.53 Hz, 1H) 5.62 (t, J=7.02 Hz, 1H)4.75 (dd, J=14.34, 4.88 Hz, 1H) 4.58 (dd, J=13.89, 8.39 Hz, 1H) 4.11 (d,J=2.14 Hz, 3H) 3.73-3.91 (m, 4H) 1.40 (dd, J=10.38, 6.71 Hz, 3H) 1.06(ddd, J=7.78, 3.05, 2.90 Hz, 1H) 0.69 (dt, J=8.62, 4.39 Hz, 1H)0.51-0.64 (m, 1H) 0.38 (ddd, J=14.50, 9.77, 4.73 Hz, 1H) 0.32 (dd,J=9.61, 4.73 Hz, 1H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 117A and 117B as free amines LC-MS (M+H)⁺=585.1. ¹HNMR (500 MHz, MeOD) δ ppm 7.73 (d, J=2.14 Hz, 1H) 7.56-7.68 (m, 3H) 7.44(d, J=8.24 Hz, 2H) 7.19 (d, J=1.53 Hz, 1H) 7.09 (d, J=8.55 Hz, 1H) 6.94(dd, J=8.55, 2.14 Hz, 1H) 4.65-4.72 (m, 1H) 4.52-4.62 (m, 1H) 4.16 (dd,J=11.44, 4.73 Hz, 1H) 3.92 (dd, J=11.29, 4.88 Hz, 1H) 3.89 (dd, J=8.24,6.71 Hz, 1H) 3.49 (s, 3H) 3.06 (q, J=7.32 Hz, 1H) 1.22-1.41 (m, 3H) 1.08(dt, J=8.24, 4.88 Hz, 1H) 0.51-0.59 (m, 1H) 0.48 (dd, J=8.39, 5.04 Hz,1H) 0.39 (dd, J=9.77, 4.58 Hz, 1H) 0.19-0.33 (m, 1H).

Example 118N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA

2-chloro-N-ethyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Za) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (Example 118). LC-MS (M+H)⁺=545.3. ¹H NMR (500 MHz, CDCl₃) δ ppm11.87 (s, 1H) 7.68 (d, J=1.22 Hz, 1H) 7.59 (m, 4H) 7.49 (d, J=2.14 Hz,1H) 7.40 (dd, J=8.55, 2.14 Hz, 1H) 7.20 (d, J=8.55 Hz, 1H) 7.11 (d,J=1.53 Hz, 1H) 6.38 (br. s., 1H) 4.76 (d, J=14.34 Hz, 1H) 4.57 (d,J=13.73 Hz, 1H) 4.07-4.16 (m, 3H) 3.86 (s, 3H) 3.59-3.77 (m, 2H) 1.36(t, J=7.17 Hz, 3H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 118A and 118B as free amines LC-MS (M+H)⁺=545.1. ¹HNMR (500 MHz, MeOD) δ ppm 7.79 (d, J=1.83 Hz, 1H) 7.56-7.70 (m, 3H) 7.43(d, J=7.93 Hz, 2H) 7.19 (d, J=1.53 Hz, 1H) 7.11 (d, J=8.55 Hz, 1H)6.91-7.03 (m, 1H) 4.60-4.72 (m, 1H) 4.48-4.60 (m, 1H) 4.15 (dd, J=11.14,4.43 Hz, 1H) 3.99 (t, J=4.27 Hz, 1 H) 3.87-3.97 (m, 1H) 3.46-3.66 (m,5H) 1.28 (t, J=7.17 Hz, 3H).

Example 119N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA

2-chloro-N-ethyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Za) was reacted as described in Example 112 with3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation C) togiveN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (Example 119). LC-MS (M+H)⁺=514.3. ¹H NMR (500 MHz, CDCl₃) δ ppm12.20 (br. s., 1H) 8.01 (s, 1H) 7.93 (dd, J=12.36, 2.29 Hz, 1H) 7.59 (m,4H) 7.52 (dd, J=8.85, 1.53 Hz, 1H) 7.38 (t, J=8.39 Hz, 1H) 5.97 (br. s.,1H) 4.72 (d, J=14.34 Hz, 1H) 4.54 (d, J=13.73 Hz, 1H) 3.99-4.18 (m, 3H)3.57-3.75 (m, 2H) 2.43 (s, 3H) 1.37 (t, J=7.17 Hz, 3H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 119A and 119B as free amines LC-MS (M+H)⁺=514.1. ¹HNMR (500 MHz, MeOD) δ ppm 8.02 (s, 1H) 8.00 (dd, J=14.04, 2.14 Hz, 1H)7.62 (m, J=8.24 Hz, 2H) 7.48 (m, J=8.24 Hz, 2H) 7.21-7.34 (m, 2H)4.62-4.72 (m, 1H) 4.52-4.62 (m, 1H) 4.15-4.27 (m, 1H) 3.94-4.09 (m, 2H)3.58 (q, J=7.32 Hz, 2H) 2.36 (s, 3H) 1.30 (t, J=7.17 Hz, 3H).

Example 120N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA

2-chloro-N-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(Preparation Zb) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine,TFA (Example 120). LC-MS (M+H)⁺=531.3. ¹H NMR (500 MHz, CDCl₃) δ ppm11.80 (s, 1H) 7.87 (d, J=1.53 Hz, 1 H) 7.51-7.63 (m, 5H) 7.40 (dd,J=8.85, 2.14 Hz, 1H) 7.28 (s, 1H) 7.20 (d, J=8.55 Hz, 1 H) 6.56 (d,J=4.58 Hz, 1H) 4.76 (d, J=14.34 Hz, 1H) 4.57 (d, J=14.04 Hz, 1H)4.01-4.14 (m, 3H) 3.87 (s, 3H) 3.21 (d, J=4.58 Hz, 3H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 120A and 120B as free amines. LC-MS (M+H)⁺=531.1. ¹HNMR (500 MHz, MeOD) δ ppm 7.86 (d, J=2.14 Hz, 1H) 7.65 (d, J=1.53 Hz,1H) 7.60 (m, J=7.93 Hz, 2H) 7.43 (m, J=7.93 Hz, 2H) 7.19 (d, J=1.53 Hz,1H) 7.11 (d, J=8.55 Hz, 1H) 6.96 (dd, J=8.55, 2.14 Hz, 1H) 4.59-4.68 (m,1H) 4.48-4.56 (m, 1H) 4.15 (dd, J=11.29, 4.58 Hz, 1H) 3.98-4.03 (m, 1H)3.92 (dd, J=11.29, 4.88 Hz, 1H) 3.52 (s, 3H) 3.04 (s, 3H).

Example 1214-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile,TFA

4-(2-chloro-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile(Preparation AAa) was reacted as described in Example 112 with4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) to give4-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile,TFA (Example 121). LC-MS (M+H)⁺=502.3. ¹H NMR (500 MHz, CDCl₃) δ ppm11.80 (s, 1H) 7.93 (s, 1H) 7.61-7.66 (m, 2H) 7.55-7.61 (m, 2H) 7.48 (d,J=1.83 Hz, 1H) 7.41 (dd, J=8.55, 2.14 Hz, 1H) 7.22 (d, J=8.85 Hz, 1H)7.15 (d, J=1.53 Hz, 1H) 6.22 (t, J=5.34 Hz, 1H) 4.76 (d, J=14.34 Hz, 1H)4.57 (d, J=14.34 Hz, 1H) 4.09 (s, 3H) 3.87 (s, 3H) 3.66-3.75 (m, 2H)1.37 (t, J=7.32 Hz, 3H).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 121A and 121B as free amines LC-MS (M+H)⁺=502.1. ¹HNMR (500 MHz, MeOD) δ ppm 7.80 (d, J=2.14 Hz, 1H) 7.67 (d, J=2.14 Hz,2H) 7.66 (br. s., 1H) 7.45 (d, J=8.24 Hz, 2H) 7.22 (s, 1H) 7.13 (d,J=8.55 Hz, 1H) 6.98-7.05 (m, 1H) 4.62-4.69 (m, 1H) 4.51-4.57 (m, 1H)4.15 (dd, J=10.99, 3.97 Hz, 1H) 3.91-4.02 (m, 2H) 3.54-3.64 (m, 5H) 1.28(t, J=7.17 Hz, 3H).

Example 122N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

To a mixture of2-chloro-N-methyl-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine(69.8 mg, 0.194 mmol), 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(Preparation A)(52.1 mg, 0.233 mmol), XANTPHOS (11.23 mg, 0.019 mmol),Pd2(dba)₃ (8.88 mg, 9.70 μmol), and Cs₂CO₃ (190 mg, 0.582 mmol) wasadded Dioxane (808 μL). The mixture was flushed with Nitrogen and placedin a capped vial and heated at 100° C. overnight.

Cooled the reaction to rt and diluted with EtOAc. Filtered through aCelite plug and rotovaped. The residue was placed on Silica gel andeluted with an EtOAc/Hex gradient to obtainN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamineLC-MS (M+H)⁺=547.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.78 (1H, s), 7.48(1H, s), 7.25-7.29 (2H, m), 7.11-7.20 (2H, m), 6.94-7.09 (3H, m), 6.77(1H, d, J=8.55 Hz), 4.50-4.67 (2H, m), 4.32 (1H, d, J=4.88 Hz),4.07-4.19 (1H, m), 3.89-4.01 (2H, m), 3.52 (3H, s), 3.09 (3H, d, J=4.58Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 122A and 122B, which had identical spectral data.

Examples 123A and 123BN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(R)-3-fluoropyrrolidin-1-yl)-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine

Individual Diasteriomers

To a mixture of2-chloro-4-((R)-3-fluoropyrrolidin-1-yl)-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine(57.6 mg, 0.138 mmol), 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(Preparation A) (37.0 mg, 0.165 mmol), XANTPHOS (7.98 mg, 0.014 mmol),Pd2(dba)3 (6.31 mg, 6.89 μmol), and Cs2CO3 (135 mg, 0.414 mmol) wasadded Dioxane (574 μL). The mixture was flushed with Nitrogen and placedin a capped vial and heated at 100° C. overnight. The reaction wascooled to rt and diluted with EtOAc, then filtered through a Celite plugand concentrated. The residue was placed on Silica gel and eluted withan EtOAc/Hex gradient to obtain 2 diasteriomers (Examples 123A and123B).

123A: LC-MS (M+H)⁺=605.3. ¹H NMR (500 MHz, MeOD) δ ppm 7.79 (1H, d,J=1.53 Hz), 7.46-7.53 (3H, m), 7.32-7.41 (4H, m), 7.19 (1H, dd, J=8.55,2.14 Hz), 5.43 (1H, d, J=52.50 Hz), 5.12-5.18 (1H, m), 4.99 (1H, d,J=14.34 Hz), 3.98-4.33 (6 H, m), 3.87 (3H, s), 3.81 (1H, dd, J=10.68,6.41 Hz), 2.37-2.49 (1H, m), 2.15-2.33 (1H, m).

123B: LC-MS (M+H)⁺=605.3. ¹H NMR (500 MHz, CDCl₃) ppm 7.56 (1H, d,J=1.83 Hz), 7.48 (1H, d, J=1.53 Hz), 7.22-7.28 (2H, m), 7.14 (2H, d,J=8.24 Hz), 7.04 (1H, d, J=8.55 Hz), 6.99 (1H, d, J=1.22 Hz), 6.82 (1H,dd, J=8.55, 1.83 Hz), 5.33 (1H, d, J=52.80 Hz), 4.90-5.00 (2H, m),4.16-4.26 (1H, m), 4.10 (1H, dd, J=11.44, 4.43 Hz), 3.80-4.01 (5H, m),3.50 (3H, s), 2.32-2.43 (1H, m), 2.00-2.19 (1H, m).

Example 124N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine

To a solution of2-chloro-N-ethyl-N-methyl-8-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine(42.9 mg, 0.142 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(31.8 mg, 0.142 mmol) in THF (2 mL) was added 60% suspension of sodiumhydride in mineral oil (6.82 mg, 0.284 mmol). The reaction mixture washeated with stirring in a capped vial at 80° C. for 1.5 h. The reactionmixture was carefully partitioned between an aqueous solution ofammonium chloride and dichloromethane. The organic layer was separatedand the aqueous layer was extracted with dichloromethane. The combinedorganic extracts were dried over anhydrous magnesium sulfate andfiltered. The solvent was removed in vacuum and the residue was purifiedby reverse-phase preparative HPLC to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine(31.6 mg, 0.048 mmol, 33.5% yield) as brown oil. LC-MS (M+H)⁺=489.2. ¹HNMR (500 MHz, CDCl₃) δ ppm 11.50 (1H, br s), 7.74 (1H, d, J=1.2 Hz),7.39 (1H, dd, J=8.5, 2.1 Hz), 7.29 (2H, dd, J=4.9, 2.7 Hz), 7.21-7.27(2H, m), 7.12-7.19 (3H, m), 7.07 (1H, d, J=1.5 Hz), 4.20 (1H, t, J=7.0Hz), 3.80 (3H, s), 3.68-3.78 (2H, m, J=13.8, 7.0, 7.0, 7.0, 7.0 Hz),3.31 (3H, s), 2.64-2.82 (2H, m), 2.27 (1H, ddd, J=13.3, 7.5, 5.2 Hz),1.88-1.99 (1H, m), 1.74-1.85 (1H, m), 1.54-1.67 (1H, m), 1.34 (3H, t,J=7.0 Hz).

Examples 124A and 124B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine

A racemic mixture ofN²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine(183 mg, 0.206 mmol from Example 124) was purified using chiralsupercritical fluid chromatography (SFC) to afford 54.7 mg of peak A(Example 124A) and 53.3 mg of peak B (Example 124B). SFC Method:Chiralpak OJ-H (30×250 mm, 5 μM), 30% methanol (0.1% diethylamine) inCO₂, 35° C., flow rate 70 mL/min for 105 min, absorbance 220 nm,injection 0.75 mL of 26 mg/mL solution in methanol (multiple stackedinjections), t_(R) (peak A)=4.9 min, t_(R) (peak B) 12.0 min. Theabsolute stereochemistry of individual enantiomers (Examples 124A and124B) were not determined. LC-MS and ¹H NMR analytical data for theseparated enantiomers was identical to the racemate (Example 124).

Example 125N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-phenyl-5,6,7,8-tetrahydroquinazolin-2-amine

To a solution of 2-chloro-8-phenyl-5,6,7,8-tetrahydroquinazoline (33.0mg, 0.135 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (33.2mg, 0.148 mmol) in THF (1.5 mL) in a 2.0-5.0 mL microwave tube was added0.5 M solution of KHMDS in toluene (0.809 mL, 0.405 mmol). The tube wassealed and the reaction mixture was stirred at 100° C. in a microwavefor 2 h. The reaction mixture was diluted with methanol and purifiedusing reverse-phase preparative HPLC method. The solvent was removed invacuum and the residue was purified by reverse-phase preparative HPLC togiveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine(31.6 mg, 0.048 mmol, 33.5% yield) as brown oil. LC-MS (M+H)⁺=432.3. ¹HNMR (500 MHz, CDCl₃) δ ppm 11.68 (1H, s), 8.25 (1H, s), 8.14 (1H, s),7.32-7.39 (3H, m), 7.26-7.32 (1H, m), 7.05-7.12 (3H, m), 6.96-7.04 (2H,m), 4.20 (1H, t, J=7.2 Hz), 3.41 (3H, s), 2.80-2.94 (2H, m), 2.30-2.40(1H, m), 1.97-2.12 (2H, m), 1.81-1.93 (1H, m).

Example 126N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-8-(4-fluorophenyl)-N⁴-methyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine

2-Chloro-N-ethyl-8-(4-fluorophenyl)-N-methyl-5,6,7,8-tetrahydroquinazolin-4-amine(124 mg, 0.388 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (87 mg, 0.388 mmol) inTHF (1 mL) and Acetic Acid (1.000 mL). The reaction mixture was stirredovernight at 75° C. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-8-(4-fluorophenyl)-N⁴-methyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine,TFA salt (101.3 mg, 0.153 mmol, 39.5% yield). LC-MS (M+H)⁺=507.2. ¹H NMR(500 MHz, CDCl₃) δ ppm 10.77-11.01 (1H, m), 7.95-8.15 (1H, m), 7.33-7.44(1H, m), 7.22-7.24 (1H, m), 7.19 (1H, d, J=8.5 Hz), 7.12-7.16 (2H, m),6.96-7.03 (2H, m), 4.09-4.21 (1H, m), 3.96 (1H, s), 3.81 (4H, s),3.67-3.79 (3H, m), 3.32 (3H, s), 2.19-2.33 (1H, m), 1.88-1.99 (1H, m),1.71-1.81 (1H, m), 1.56-1.69 (1H, m), 1.26-1.38 (3H, m).

Example 127N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N⁴,N⁴-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine

2-Chloro-8-(4-fluorophenyl)-N,N-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine(118 mg, 0.386 mmol) was added to a solution of4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (95 mg, 0.424 mmol) inTHF (1 mL) and acetic acid (1.000 mL). The reaction mixture was stirredovernight at 75° C. The crude reaction mixture was purified bypreparative HPLC. The appropriate fractions were evaporated to affordN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N⁴,N⁴-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine,TFA salt (74.8 mg, 0.123 mmol, 31.9% yield). LC-MS (M+H)⁺=493.2. ¹H NMR(500 MHz, CDCl₃) δ ppm 11.69 (1H, s), 7.59 (1H, d, J=1.2 Hz), 7.36 (2H,d, J=2.1 Hz), 7.14 (3H, d, J=9.2 Hz), 7.05 (1H, d, J=1.5 Hz), 6.99 (2H,s), 4.17-4.27 (1H, m), 3.81 (3H, s), 3.47 (1H, s), 3.36 (5H, s),2.65-2.84 (2H, m), 2.21-2.33 (1H, m), 1.87-1.98 (1H, m), 1.69-1.81 (1H,m), 1.53-1.67 (1H, m).

Examples 127A & 127B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N⁴,N⁴-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N⁴,N⁴-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N⁴,N⁴-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine(Example 127) was purified using chiral SFC to afford peak A (Example127A) and peak B (Example 127B). SFC Method: Chiralpak OJ-H (4.6×250 mm,5 μM), 30% methanol (0.1% diethylamine) in CO₂, 35° C., flow rate 2.0mL/min for 13 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solutionin methanol (multiple stacked injections), t_(R) (peak A)=4.3 min, t_(R)(peak B) 9.6 min. The absolute stereochemistry of individual enantiomers(Examples 7 and 8) was not determined LC-MS and ¹H NMR analytical datafor the separated enantiomers was identical to the racemate (Example127).

Example 128N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine

To a solution of2-chloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (20 mg, 0.076mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (18.73 mg,0.084 mmol) in THF (1.5 mL) in a 2.0-5.0 mL microwave tube, was added a0.5 M solution of KHMDS (0.167 mL, 0.084 mmol). The tube was sealed andthe reaction mixture was stirred at 100° C. in a microwave for 2 h. Thereaction mixture was diluted with methanol and purified usingpreparative HPLC. The appropriate fractions were evaporated to affordN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine,TFA salt (0.7 mg, 1.229 μmol, 1.614% yield). LC-MS (M+H)⁺=450.2. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.14-8.26 (1H, m), 7.56-7.62 (1H, m), 7.43-7.48(1H, m), 7.28-7.31 (1H, m), 7.21 (1H, s), 6.98-7.10 (6H, m), 6.88-6.94(1H, m), 4.08-4.18 (1H, m), 2.77-2.83 (3H, m), 2.23-2.32 (1H, m),1.91-2.13 (3H, m), 1.25 (1H, s).

Example 129N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEj (0.2 g, 0.433 mmol) in dichloromethanewas added diisopropylethylamine (0.11 g, 0.867 mmol) at −10° C. followedby addition of methane sulfonyl chloride (0.055 g, 0.477 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with dichloromethane, washed with water, evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) togiveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.105 g, 48%) as off-white solid. LC-MS (M+H)⁺=540.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.20 (1H, s), 8.03 (1H, s), 7.72 (1H, s), 7.41 (1H, s),7.31-7.03 (8H, m), 4.21 (1H, m), 4.11 (2H, m), 3.60-3.47 (5H, m), 2.96(3H, d, J=4.4 Hz), 2.89 (3H, s). The example was separated by chiralchromatography to afford the enantiomers 129A and 129B, which hadidentical spectral data.

Example 130N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-6-(cyclopropylsulfonyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEj (0.32 g, 0.693 mmol) in dichloromethanewas added diisopropylethylamine (0.18 g, 1.38 mmol) at −10° C. followedby addition of cyclopropyl sulfonyl chloride (0.117 g, 0.832 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with dichloromethane, washed with water, evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) togiveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-6-(cyclopropylsulfonyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.11 g, 35%) as white solid. LC-MS (M+H)⁺=566.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.18 (1H, s), 8.03 (1H, s), 7.72 (1H, s), 7.40 (1H, s),7.31-7.04 (8H, m), 4.26 (1H, m), 4.10 (2H, m), 3.68 (1H, m), 3.68-3.65(4H, m), 2.98 (3H, d, J=4.4 Hz), 2.54 (1H, m), 0.95 (4H, m).

The example was separated by chiral chromatography to afford theenantiomers 130A and 130B, which had identical spectral data.

Example 131 Methyl2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

To a solution of Preparation AEk (0.15 g, 0.3 mmol) in dichloromethanewas added diisopropylethylamine (0.081 g, 0.6 mmol) at −10° C. followedby addition of methylchloro formate (0.044 g, 0.3 mmol). The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with dichloromethane, washed with water, evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to givemethyl2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate(0.12 g, 68%) as white solid. LC-MS (M−H)⁺=532.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.16 (1H, s), 7.98 (1H, s), 7.73 (1H, s), 7.42 (1H, s),7.29-7.26 (2H, m), 7.21-7.12 (5H, m), 7.05 (1H, m), 4.62 (1H, m), 4.23(1H, m), 3.96-3.87 (3H, m), 3.68-3.51 (8H, m), 1.23 (3H, t, J=8.0 Hz).

The example was separated by chiral chromatography to afford theenantiomers 131A and 131B, which had identical spectral data.

Example 132(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(cyclopropyl)methanone

To a solution of Preparation AEk (0.35 g, 0.73 mmol) in dichloromethanewas added diisopropylethylamine (0.14 g, 1.1 mmol) at −10° C. followedby addition of cyclopropylcarbonyl chloride (0.085 g, 0.81 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with dichloromethane, washed with water, evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by prep-HPLC (aqueous 0.1% ammonium acetate in methanol) togive(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(cyclopropyl)methanone(0.12 g, 30%) as white solid. LC-MS (M+H)⁺=544.2. ¹H NMR (400 MHz,CDCl₃6): δ ppm 7.70 (1H, s), 7.51 (1H, s), 7.31-7.23 (3H, m), 7.12-6.99(4H, m), 6.93 (1H, bs), 5.05 (1H, m), 4.22 (1H, m), 4.07 (1H, m), 3.99(1H, m), 3.63 (1H, m), 3.59 (5H, m), 1.33 (3H, t, J=7.2 Hz), 1.25 (1H,m), 0.87 (1H, m), 0.84 (2H, m), 0.63 (1H, m).

The example was separated by chiral chromatography to afford theenantiomers 132A and 132B, which had identical spectral data.

Example 1331-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxyethanone

To a solution of Preparation AEk (0.187 g, 0.39 mmol) in dichloromethanewas added triethylamine (0.79 g, 0.78 mmol) at −10° C. followed byaddition of methoxyacetyl chloride (0.043 g, 0.42 mmol). The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with dichloromethane, washed with water, evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to give1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxyethanone(0.10 g, 57%) as off-white solid. LC-MS (M+H)⁺=548.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.19 (1H, s), 7.99 (1H, s), 7.73 (1H, 1), 7.42 (1H, s),7.32-7.09 (8H, m), 4.86 (1H, m), 4.20 (2H, m), 4.09 (2H, m), 4.02-3.50(5H, m), 3.31 (1H, m), 3.18 (1H, m), 2.99 (3H, s), 1.23 (3H, t, J=7.2Hz).

The example was separated by chiral chromatography to afford theenantiomers 133A and 133B, which had identical spectral data.

Example 134N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEk (0.10 g, 0.21 mmol) in dichloromethanewas added diisopropylethylamine (0.054 g, 0.42 mmol) at −10° C. followedby addition of methanesulfonyl chloride (0.024 g, 0.21 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with dichloromethane, washed with water, evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) togiveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.06 g, 54%) as off-white solid. LC-MS (M+H)⁺=554.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.17 (1H, s), 7.96 (1H, s), 7.73 (1H, s), 7.42 (1H, s),7.32-7.20 (5H, m), 7.16-7.10 (2H, m), 6.98 (1H, m), 4.22 (1H, m),4.11-4.03 (2H, m), 3.62-3.49 (7H, m), 2.91 (3H, s), 1.23 (3H, t, J=7.2Hz).

The example was separated by chiral chromatography to afford theenantiomers 134A and 134B, which had identical spectral data.

Example 1351-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(dimethylamino)ethanone

To a solution of Preparation AEk (0.15 g, 0.31 mmol) in dichloromethanewas added triethylamine (0.079 g, 0.78 mmol) at −10° C. followed byaddition of N,N-dimethylamionoacetyl chloride.HCl (0.054 g, 0.34 mmol).The reaction mixture was stirred at room temperature for 1 h. Thereaction mixture was diluted with dichloromethane, washed with water,evaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (aqueous 0.1% ammonium acetate inacetonitrile) to give1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(dimethylamino)ethanone(0.11 g, 72%) as off-white solid. LC-MS (M+H)⁺=561.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.16 (1H, s), 7.98 (1H, s), 7.72 (1H, s), 7.40 (1H, s),7.31-7.11 (7H, m), 7.07 (1H, m), 4.77 (1H, m), 4.06 (2H, m), 3.94 (1H,m), 3.60 (1H, m), 3.52-3.42 (5H, m), 2.72 (1H, m), 2.28 (1H, m), 2.15(6H, s), 1.20 (3H, m). The example was separated by chiralchromatography to afford the enantiomers 135A and 135B, which hadidentical spectral data.

Example 136N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-6-(cyclopropylsulfonyl)-N4-ethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEk (0.15 g, 0.31 mmol) in dichloromethanewas added diisopropylethylamine (0.77 g, 0.62 mmol) at −10° C. followedby addition of cyclopropanesulfonyl chloride (0.042 g, 0.31 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with dichloromethane, washed with water, evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by prep-HPLC (aqueous 0.1% ammonium acetate in methanol) togiveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-6-(cyclopropylsulfonyl)-N4-ethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.10 g, 55%) as off-white solid. LC-MS (M+H)⁺=578.2. ¹H NMR (400 MHz,CDCl₃): δ ppm 9.15 (1H, s), 7.95 (1H, s), 7.72 (1H, s), 7.41 (1H, s),7.29 (2H, m), 7.21 (3H, m), 7.14 (2H, m), 7.01 (1H, bs), 4.26 (1H, m),4.11 (2H, m), 3.65 (1H, m), 3.56-3.51 (6H, m), 2.5 (1H, m), 1.23 (5H,m), 0.97 (2H, m).

The example was separated by chiral chromatography to afford theenantiomers 136A and 136B, which had identical spectral data.

Example 1371-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone

To a solution of Preparation AEk (0.15 g, 0.31 mmol) in dichloromethanewas added diisopropylethylamine (0.77 g, 0.62 mmol) at −10° C. followedby addition of acetyl chloride (0.027 g, 0.31 mmol). The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with dichloromethane, washed with water, evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in methanol) to give1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone(0.09 g, 57%) as off-white solid. LC-MS (M+H)⁺=518.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.19 (1H, s), 8.00 (1H, s), 7.74 (1H, s), 7.42 (1H, s),7.28 (3H, m), 7.17-7.07 (5H, m), 4.91 (1H, m), 4.06 (1H, m), 3.93 (1H,m), 3.82 (2H, m), 3.58-3.50 (5H, m), 1.47 (3H, s), 1.23 (3H, m).

The example was separated by chiral chromatography to afford theenantiomers 137A and 137B, which had identical spectral data.

Example 138N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-(ethylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEk (0.15 g, 0.31 mmol) in dichloromethanewas added diisopropylethylamine (0.77 g, 0.62 mmol) at −10° C. followedby addition of ethanesulfonyl chloride (0.038 g, 0.31 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with dichloromethane, washed with water, evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by prep-HPLC (aqueous 0.1% ammonium acetate in methanol) togiveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-(ethylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.11 g, 62%) as off-white solid. LC-MS (M−H)⁺=566.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.17 (1H, s), 7.96 (1H, s), 7.73 (1H, s), 7.42 (1H, s),7.31 (2H, m), 7.28 (3H, m), 7.21 (2H, m), 6.97 (1H, m), 4.25 (1H, m),4.13-4.05 (2H, m), 3.60 (1H, m), 3.58-3.50 (6H, m), 3.05 (2H, m), 1.23(3H, t, J=8.0 Hz), 1.17 (3H, t, J=7.2 Hz).

The example was separated by chiral chromatography to afford theenantiomers 138A and 138B, which had identical spectral data.

Example 139N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEm (0.20 g, 0.450 mmol) in dichloromethanewas added diisopropylethylamine (0.11 g, 0.90 mmol) at −10° C. followedby addition of methanesulfonyl chloride (0.05 g, 0.450 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with dichloromethane, washed with water, evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) togiveN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.048 g, 20%) as off-white solid. LC-MS (M+H)⁺=523.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.44 (1H, s), 8.67 (1H, s), 8.00 (1H, m), 7.42 (2H, m),7.39 (2H, m), 7.32 (3H, m), 7.05 (1H, m), 4.20 (1H, m), 4.08 (2H, m),3.63 (1H, m), 3.55-3.46 (3H, m), 2.92 (3H, s), 2.33 (3H, s), 1.24 (3H,t, J=7.2 Hz).

The example was separated by chiral chromatography to afford theenantiomers 139A and 139B, which had identical spectral data.

Example 140N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEo (0.25 g, 0.560 mmol) in dichloromethanewas added diisopropylethylamine (0.145 g, 1.120 mmol) at −10° C.followed by addition of methanesulfonyl chloride (0.06 g, 0.560 mmol).The reaction mixture was stirred at room temperature for 1 h. Thereaction mixture was diluted with dichloromethane, washed with water,evaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (aqueous 0.1% ammonium acetate inacetonitrile) to giveN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.05 g, 22%) as off-white solid. LC-MS (M−H)⁺=521.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.47 (1H, s), 8.00 (2H, m), 7.44 (1H, m), 7.33-7.22 (6H,m), 7.05 (1H, m), 4.21 (1H, m), 4.11-4.07 (2H, m), 3.63 (1H, m),3.57-3.50 (3H, m), 2.93 (3H, s), 2.27 (3H, s), 1.24 (3H, t, J=7.2 Hz).

The example was separated by chiral chromatography to afford theenantiomers 140A and 140B, which had identical spectral data.

Example 1416-(cyclopropylsulfonyl)-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEl(0.23 g, 0.534 mmol) in dichloromethanewas added diisopropylethylamine (0.138 g, 1.060 mmol) at −10° C.followed by addition of cyclopropanesulfonyl chloride (0.089 g, 0.640mmol). The reaction mixture was stirred at room temperature for 1 h. Thereaction mixture was diluted with dichloromethane, washed with water,evaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (aqueous 0.1% ammonium acetate inmethanol) to give6-(cyclopropylsulfonyl)-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.11 g, 50%) as off-white solid. LC-MS (M+H)⁺=535.2. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 9.45 (1H, s), 8.68 (1H, s), 8.03 (1H, m), 7.22 (2H, m),7.32-7.21 (5H, m), 7.11 (1H, m), 4.25 (1H, m), 4.13 (1H, m), 4.08 (1H,m), 3.71 (1H, m), 3.64 (1H, m), 2.96 (3H, d, J=4.0 Hz), 2.58 (1H, m),2.33 (3H, s), 1.01-0.95 (4H, m).

The example was separated by chiral chromatography to afford theenantiomers 141A and 141B, which had identical spectral data.

Example 1426-(cyclopropylsulfonyl)-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEm (0.30 g, 0.690 mmol) in dichloromethanewas added diisopropylethylamine (0.180 g, 1.39 mmol) at −10° C. followedby addition of cyclopropanesulfonyl chloride (0.117 g, 0.830 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with dichloromethane, washed with water, evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by prep-HPLC (aqueous 0.1% ammonium acetate in methanol) togive6-(cyclopropylsulfonyl)-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.14 g, 45%) as off-white solid. LC-MS (M+H)⁺=535.2. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 9.49 (1H, s), 8.02 (2H, m), 7.46 (1H, m), 7.44-7.33 (3H,m), 7.30-7.21 (3H, m), 7.11 (1H, m), 4.26 (1H, m), 4.15 (1H, m), 4.10(1H, m), 3.73 (1H, m), 3.59 (1H, m), 3.28 (3H, m), 2.59 (1H, m), 2.27(3H, s), 1.24-1.0 (4H, m).

Example 143cyclopropyl(4-(ethylamino)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone

To a solution of Preparation AEm (0.21 g, 0.49 mmol) in dichloromethanewas added diisopropylethylamine (0.12 g, 0.70 mmol) at −10° C. followedby addition of cyclopropylcarbonyl chloride (0.056 g, 0.54 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with dichloromethane, washed with water, evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by prep-HPLC (aqueous 0.1% ammonium acetate in methanol) togivecyclopropyl(4-(ethylamino)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone(0.090 g, 38%) as white solid. LC-MS (M+H)⁺=513.4. ¹H NMR (400 MHz,CDCl₃6): δ ppm 8.41 (1H, s), 7.94 (1H, m), 7.63 (1H, m), 7.32 (3H, m),7.27 (1H, m), 7.10 (2H, m), 4.97 (1H, m), 4.21 (1H, m), 4.10-4.0 (2H,m), 3.91 (1H, m), 3.63 (2H, m), 2.48 (3H, s), 1.35 (3H, t, J=7.2 Hz),1.22 (1H, m), 0.85 (1H, m), 0.65-0.62 (2H, m), 0.34 (1H, m). The examplewas separated by chiral chromatography to afford the enantiomers 143Aand 143B, which had identical spectral data.

Example 144cyclopropyl(4-(ethylamino)-2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone

To a solution of Preparation AEo (0.30 g, 0.67 mmol) in dichloromethanewas added diisopropylethylamine (0.17 g, 1.35 mmol) at −10° C. followedby addition of cyclopropylcarbonyl chloride (0.084 g, 0.81 mmol). Thereaction mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with dichloromethane, washed with water, evaporatedunder reduced pressure to get crude compound. The crude compound waspurified by prep-HPLC (aqueous 0.1% ammonium acetate in methanol) tocyclopropyl(4-(ethylamino)-2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone(0.14 g, 41%) as white solid. LC-MS (M+H)⁺=513.4. ¹H NMR (400 MHz,CDCl₃6): δ ppm 7.94 (2H, m), 7.32-7.25 (4H, m), 7.13 (3H, m), 4.96 (1H,m), 4.22 (1H, m), 4.13-4.04 (2H, m), 3.93 (1H, m), 3.63 (2H, m), 2.39(3H, s), 1.35 (3H, t, J=7.2 Hz), 1.26 (1H, m), 0.87 (1H, m), 0.66 (2H,m), 0.38 (1H, m).

The example was separated by chiral chromatography to afford theenantiomers 144A and 144B, which had identical spectral data.

Example 145N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEp (0.20 g, 0.37 mmol) in THF was addedborane-DMS (0.061 g, 0.814 mmol, 2M in diethyl ether) at −0° C. Thereaction mixture was heated at 55° C. for 18 h. The reaction mixture wasquenched with methanol and evaporated the solvent under reduced pressureto get crude compound. The crude compound was purified by prep-HPLC(aqueous 0.1% ammonium acetate in acetonitrile) get crude to giveN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.025 g, 14%) as yellow solid. LC-MS (M+H)⁺=527.2. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 9.32 (1H, s), 8.67 (1H, s), 8.03 (1H, m), 7.41-7.38 (2H,m), 7.27-7.18 (5H, m), 6.83 (1H, m), 3.97 (1H, m), 3.73 (1H, m), 3.57(1H, m), 3.45 (2H, m), 3.37 (2H, m), 3.18 (1H, m), 2.97 (1H, m), 2.33(3H., s), 1.23 (3H, t, J=7.2 Hz).

Example 146N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AEq (0.22 g, 0.40 mmol) in THF was addedborane-DMS (0.068 g, 0.89 mmol, 2 M in diethyl ether) at −0° C. Thereaction mixture was heated at 55° C. for 18 h. The reaction mixture wasquenched with methanol and evaporated the solvent under reduced pressureto get crude compound. The crude compound was purified by prep-HPLC(aqueous 0.1% ammonium acetate in acetonitrile) get crude to giveN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.030 g, 15%) as yellow solid. LC-MS (M+H)⁺=527.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.37 (1H, s), 8.04 (1H, s), 8.00 (1H, m), 7.42 (1H, m),7.30-7.20 (6H, m), 6.84 (1H, m), 3.98 (1H, m), 3.73 (1H, m), 3.69 (1H,m), 3.57-3.48 (4H, m), 3.23 (1H, m), 2.99 (1H, m), 2.26 (3H., s), 1.23(3H, t, J=7.2 Hz).

Example 147N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,N4-dimethyl-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

Using the methods of Preparation AEd, Preparation AEj, and Example 134,Preparation AEc was transformed intoN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,N⁴-dimethyl-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine.LC-MS (M−H)⁺=552.2. ¹H NMR (400 MHz, DMSO-d6): δ ppm 9.27 (1H, s), 7.91(1H, s), 7.73 (1H, m), 7.42 (1H, m), 7.31 (2H, m), 7.25-7.10 (5H, m),4.46 (1H, m), 4.30-4.24 (2H, m), 3.83 (1H, m), 3.53 (3H, s), 3.28 (1H,m), 3.13 (6H, s), 3.09 (3H, s).

Example 148N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.26 g, 1.2 mmol), Preparation AFa (0.35 g,1.2 mmol), Na₂CO₃ (0.25 g, 2.4 mmol) and xantphos (0.69 g, 1.2 mmol) indioxane/water (9:1) was purged with argon for 1 h at room temperature.Pd(dba)₃ (0.55 g, 0.6 mmol) was added to the reaction mixture and theresulting solution was purged with argon for another 1 h. The reactionmass was heated at 110° C. for 24 h. The reaction mass was filteredthrough a bed of diamataceous earth (Celite®) and washed with ethylacetate. The filtrate was evaporated under reduced pressure and theresidue was diluted with water. The aqueous solution was extracted withethyl acetate (25 mL×3). The combined organic layer was washed withbrine solution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (0.5% aqueous ammonium acetate in methanol) giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.10 g, 18%) as off-white solid. LC-MS (M+H)⁺=476.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.05 (1H, s), 8.05 (1H, s), 7.71 (1H, s), 7.40 (1H, s),7.27-7.17 (5H, m), 7.15-7.06 (2H, m), 6.76 (1H, m), 3.94 (1H, m), 3.50(3H, s), 3.39 (1H, m), 3.18 (1H, m), 2.95 (3H, d, J=4.4 Hz), 2.51 (1H,m), 2.49 (1H, m), 2.12 (3H, s).

The example was separated by chiral chromatography to afford theenantiomers 148A and 148B, which had identical spectral data.

Example 149N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation B (0.21 g, 1.1 mmol), Preparation AFa (0.35 g,1.2 mmol), Na₂CO₃ (0.25 g, 2.4 mmol) and xantphos (0.70 g, 1.1 mmol) indioxane/water (9:1) was purged with argon for 1 h at room temperature.Pd(dba)₃ (0.55 g, 0.6 mmol) was added to the reaction mixture and theresulting solution was purged with argon for another 1 h. The reactionmass was heated at 110° C. for 24 h. The reaction mass was filteredthrough a bed of diamataceous earth (Celite®) and washed with ethylacetate. The filtrate was evaporated under reduced pressure and theresidue was diluted with water. The aqueous solution was extracted withethyl acetate (25 mL×3). The combined organic layer was washed withbrine solution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (0.5% aqueous ammonium acetate in methanol) giveN²-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.2 g, 38%) as off-white solid. LC-MS (M+H)⁺=445.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.33 (1H, s), 8.67 (1H, s), 8.05 (1H, m), 7.41 (2H, m),7.3-7.20 (5H, m), 6.84 (1H, m), 3.96 (1H, m), 3.42 (1H, m), 3.25 (1H,m), 2.94 (3H, d, J=4.4 Hz), 2.92 (1H, m), 2.71 (1H, m), 2.51 (3H, s),2.40 (3H, s).

Example 150N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation C (0.23 g, 1.2 mmol), Preparation AFa (0.35 g,1.2 mmol), Na₂CO₃ (0.25 g, 2.4 mmol) and xantphos (0.69 g, 1.2 mmol) indioxane/water (9:1) was purged with argon for 1 h at room temperature.Pd(dba)₃ (0.55 g, 0.6 mmol) was added to the reaction mixture and theresulting solution was purged with argon for another 1 h. The reactionmass was heated at 110° C. for 24 h. The reaction mass was filteredthrough a bed of diamataceous earth (Celite®) and washed with ethylacetate. The filtrate was evaporated under reduced pressure and theresidue was diluted with water. The aqueous solution was extracted withethyl acetate (25 mL×3). The combined organic layer was washed withbrine solution (25 mL), dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (0.5% aqueous ammonium acetate in methanol) giveN2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.08 g, 15%) as off-white solid. LC-MS (M+H)⁺=445.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.38 (1H, s), 8.06 (1H, m), 8.00 (1H, s), 7.44 (1H, m),7.30-7.23 (5H, m), 7.18 (1H, m), 6.84 (1H, m), 3.95 (1H, m), 3.40 (1H,m), 3.22 (1H, m), 2.93 (3H, d, J=4.4 Hz), 2.90 (1H, m), 2.86 (1H, m),2.36 (3H, s), 2.26 (3H, s).

Example 151N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.26 g, 1.19 mmol), Preparation AFb (0.4 g,1.32 mmol), Na₂CO₃ (0.28 g, 2.64 mmol) and xantphos (0.76 g, 1.32 mmol)in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.60 g, 0.66 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diamataceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (50 mL×2). The combined organic layer waswashed with brine solution (50 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (0.5% aqueous ammonium acetate inmethanol) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.15 g, 24%) as off-white solid. LC-MS (M+H)⁺=490.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.01 (1H, s), 7.97 (1H, s), 7.71 (1H, s), 7.40 (1H, s),7.39-7.20 (5H, m), 7.18-7.07 (2H, m), 6.70 (1H, m), 3.95 (1H, m), 3.57(3H, s), 3.56 (2H, m), 3.47 (1H, m), 3.18 (1H, m), 2.85 (1H, m), 2.59(1H, m), 2.34 (3H, s), 1.22 (3H, t, J=7.2 Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 151A and 151B, which had identical spectral data.

Example 152N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation B (0.12 g, 0.59 mmol), Preparation AFb (0.20g, 0.66 mmol), Na₂CO₃ (0.14 g, 1.32 mmol) and xantphos (0.38 g, 0.66mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.30 g, 0.33 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diamataceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (25 mL×3). The combined organic layer waswashed with brine solution (25 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (0.5% aqueous ammonium acetate inmethanol) giveN⁴-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.03 g, 11%) as off-white solid. LC-MS (M+H)⁺=459.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.31 (1H, s), 8.67 (1H, s), 8.04 (1H, m), 7.40 (2H, m),7.29-7.17 (5H, m), 6.81 (1H, m), 3.95 (1H, m), 3.48 (2H, m), 3.43 (1H,m), 3.21 (1H, m), 2.91 (1H, m), 2.68 (1H, m), 2.38 (3H, s), 2.33 (3H,s), 1.23 (3H, t, J=7.2 Hz).

Example 153N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation C (0.15 g, 0.82 mmol), Preparation AFb (0.25g, 0.82 mmol), Na₂CO₃ (0.17 g, 1.6 mmol) and xantphos (0.42 g, 0.82mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.37 g, 0.41 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diamataceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (25 mL×3). The combined organic layer waswashed with brine solution (25 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (0.5% aqueous ammonium acetate inmethanol) giveN⁴-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.06 g, 17%) as off-white solid. LC-MS (M+H)⁺=459.2. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.93 (1H, s), 7.84 (1H, m), 7.34-7.27 (5H, m), 7.26-2.20(2H, m), 7.05 (1H, m), 4.65 (1H, m), 4.11 (1H, m), 3.61-3.54 (2H, m),3.39 (2H, m), 3.07 (1H, m), 2.81 (1H, m), 2,51 (3H, s), 2.37 (3H, s),1.34 (3H, t, J=7.2 Hz).

Example 154N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AGk (0.08 g, 0.167 mmol) in dichloromethanewas added diisopropylethylamine (0.043 g, 0.33 mmol) followed bymethanesulfonyl chloride (0.029 g, 0.167 mmol) at 0° C. The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with dichloromethane, washed with water, evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.02 g, 23%) as off-white solid. LC-MS (M+H)⁺=558.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.21 (1H, s), 8.0 (1H, s), 7.73 (1H, s), 7.42 (1H, s),7.27-7.23 (2H, m), 7.16-7.12 (4H, m), 7.05 (1H, m), 4.20 (1H, m), 4.12(1H, m), 4.05 (1H, m), 3.56 (3H, s), 3.51-3.47 (2H, m), 2.97 (3H, d,J=4.0 Hz), 2.91 (3H, s).

The example was separated by chiral chromatography to afford theenantiomers 154A and 154B, which had identical spectral data.

Example 155N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AGl (0.09 g, 0.018 mmol) in dichloromethanewas added triethylamine (0.037 g, 0.36 mmol) followed by methanesulfonylchloride (0.021 g, 0.182 mmol) at 0° C. The reaction mixture was stirredat room temperature for 1 h. The reaction mixture was diluted withdichloromethane, washed with water, evaporated under reduced pressure toget crude compound. The crude compound was purified by prep-HPLC(aqueous 0.1% ammonium acetate in acetonitrile) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.04 g, 39%) as off-white solid. LC-MS (M−H)⁺=572.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.18 (1H, s), 7.95 (1H, s), 7.73 (1H, s), 7.42 (1H, s),7.27-7.23 (2H, m), 7.17-7.12 (4H, m), 6.99 (1H, m), 4.24 (1H, d, J=14.0Hz), 4.12 (1H, m), 4.04 (1H, d, J=14.0 Hz), 3.56 (3H, s), 3.55-3.47 (4H,m), 2.92 (3H, s), 1.22 (3H, t, J=7.2 Hz).

The example was separated by chiral chromatography to afford theenantiomers 155A and 155B, which had identical spectral data.

Example 156N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AGm (0.30 g, 0.649 mmol) in dichloromethanewas added diisopropylethylamine (0.168 g, 0.29 mmol) followed bymethanesulfonyl chloride (0.07 g, 0.649 mmol) at 0° C. The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with dichloromethane, washed with water, evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to giveN4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.250 g, 71%) as off-white solid. LC-MS (M+H)⁺=541.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.45 (1H, s), 8.69 (1H, s), 8.01 (1H, m), 7.47-7.40 (2H,m), 7.39-7.26 (2H, m), 7.15-7.07 (3H, m), 4.20 (1H, m), 4.12-4.06 (2H,m), 3.63 (1H, m), 3.54-3.48 (3H, m), 2.94 (3H, s), 2.34 (3H, s), 1.22(3H, t, J=7.2 Hz).

The example was separated by chiral chromatography to afford theenantiomers 156A and 156B, which had identical spectral data.

Example 157N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AGn (0.25 g, 0.540 mmol) in dichloromethanewas added diisopropylethylamine (0.139 g, 1.080 mmol) followed bymethanesulfonyl chloride (0.06 g, 0.540 mmol) at 0° C. The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with dichloromethane, washed with water, evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to giveN4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.19 g, 73%) as off-white solid. LC-MS (M−H)⁺=541.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.48 (1H, s), 8.01 (1H, m), 7.97 (1H, 1H), 7.43 (1H, m),7.34-7.27 (3H, m), 7.15-7.11 (2H, m), 7.05 (1H, m), 4.23-4.07 (3H, m),3.63 (1H, m), 3.55-3.48 (3H, m), 2.94 (3H, s), 2.28 (3H, s), 1.24 (3H,t, J=7.2 Hz).

The example was separated by chiral chromatography to afford theenantiomers 157A and 157B, which had identical spectral data.

Example 158N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,6-diethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of Preparation AGo (0.010 g, 0.019 mmol) in ethanol wasadded triethylamine (0.004 g, 0.039 mmol) at 0° C. followed by ethyliodide (0.030 g, 0.019 mmol). The reaction mixture was heated at 80° C.for 18 h. The solvent was removed under reduced pressure and the residuewas diluted with water. The aqueous solution was extracted with ethylacetate (10 mL×3). The combined organic layer was washed with water,dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to getcrude compound. The crude compound was purified by prep-HPLC (aqueous0.1% ammonium acetate in methanol) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,6-diethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.04 g, 40%) as off-white solid. LC-MS (M+H)⁺=536.2. ¹H NMR (400 MHz,methanol-d4): δ ppm 7.80 (1H, s), 7.67 (1H, s), 7.26-7.22 (3H, m), 7.13(1H, m), 7.07-7.00 (2H, m), 6.98 (1H, m), 4.23 (1H, m), 3.75 (1H, m),3.56-3.48 (6H, m), 3.33 (1H, m), 3.28 (3H, s), 2.69-2.64 (2H, m), 2.53(1H, m), 1.34 (3H, m), 1.30 (3H, m).

Example 159N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

To a solution of Preparation AGp (0.03 g, 0.055 mmol) in acetone wasadded K₂CO₃ (0.011, 0.083 mmol) followed by methyl iodide (0.012 g,0.083 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 2 h. The solvent was removed under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (10 mL×3). The combined organic layer waswashed with water, dried over anhydrous Na₂SO₄ and evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in methanol) to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine(0.007 g, 24%). LC-MS (M+H)⁺=556.2. ¹H NMR (400 MHz, DMSO-d6): δ ppm10.50 (1H, s), 9.56 (1H, s), 7.75 (1H, s), 7.43 (1H, s), 7.33-7.30 (2H,m), 7.25-7.18 (2H, m), 7.14 (1H, m), 4.09 (1H, m), 4.82-4.76 (2H, m),4.64 (3H, m), 4.43 (3H, m), 3.88 (1H, m), 3.51 (3H, s), 2.97 (3H, s).

Example 160N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

To a solution of Preparation AGp (0.040 g, 0.073 mmol) in acetone wasadded Cs₂CO₃ (0.036 g, 0.11 mmol) followed by methanesulfonyl chloride(0.012 g, 0.11 mmol). The reaction mixture was stirred at roomtemperature for 2 h. The solvent was removed under reduced pressure andthe residue was diluted with water. The aqueous solution was extractedwith ethyl acetate (10 mL×3). The combined organic layer was washed withwater, dried over anhydrous Na₂SO₄ and evaporated under reduced pressureto get crude compound. The crude compound was purified by prep-HPLC(aqueous 0.1% ammonium acetate in methanol) to give (0.005 g, 12%) asoff-white solid. LC-MS (M+H)⁺=620.0. ¹H NMR (400 MHz, DMSO-d6): δ ppm9.47 (1H, s), 7.85 (1H, s), 7.74 (1H, s), 7.43 (1H, s), 7.30-7.26 (2H,m), 7.18-7.09 (4H, m), 4.77-4.70 (4H, m), 4.36 (1H, m), 4.24 (2H, m),3.66 (1H, m), 3.56 (3H, s), 3.44 (1H, m), 3.0 (3H, s).

The example was separated by chiral chromatography to afford theenantiomers 160A and 160B, which had identical spectral data.

Example 161N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

This compound is identical to Preparation AGo (vide supra).

Example 162N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

This compound is identical to Preparation AGp (vide supra).

The example was separated by chiral chromatography to yield theindividual enantiomers 162A and 162B, which each had identical spectraldata.

Example 163N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.109 g, 0.49 mmol), Preparation AHa (0.15g, 0.49 mmol), Na₂CO₃ (0.103 g, 0.98 mmol) and xantphos (0.283 g, 0.49mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.253 g, 0.24 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diamataceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (25 mL×3). The combined organic layer waswashed with brine solution (25 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (0.5% aqueous ammonium acetate inmethanol) giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.035 g, 14%) as off-white solid. LC-MS (M+H)⁺=494.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.07 (1H, s), 8.32 (1H, s), 8.05 (1H, s), 7.72 (1H, s),7.26 (2H, m), 7.14-7.05 (4H, m), 6.77 (1H, m), 3.96 (1H, m), 3.94 (3H,s), 3.42 (1H, m), 3.11 (1H, m), 2.92 (3H, d, J=4.4 Hz), 2.82 (1H, m),2.58 (1H, m), 2.33 (3H, s).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 163A and 163B, which had identical spectral data.

Example 164N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.146 g, 0.650 mmol), Preparation AHb(0.210 g, 0.650 mmol), Na₂CO₃ (0.139 g, 1.30 mmol) and xantphos (0.378g, 0.650 mmol) in dioxane/water (9:1) was purged with argon for 1 h atroom temperature. Pd(dba)₃ (0.338 g, 0.327 mmol) was added to thereaction mixture and the resulting solution was purged with argon foranother 1 h. The reaction mass was heated at 110° C. for 24 h. Thereaction mass was filtered through a bed of diamataceous earth (Celite®)and washed with ethyl acetate. The filtrate was evaporated under reducedpressure and the residue was diluted with water. The aqueous solutionwas extracted with ethyl acetate (50 mL×2). The combined organic layerwas washed with brine solution (50 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (0.5% aqueous ammonium acetate inmethanol) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.022 g, 22%) as off-white solid. LC-MS (M+H)⁺=508.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.07 (1H, s), 7.97 (1H, s), 7.73 (1H, s), 7.41 (1H, s),7.29-7.23 (2H, m), 7.15-7.05 (4H, m), 6.73 (1H, m), 3.96 (1H, m), 3.56(3H, s), 3.49-3.40 (3H, m), 3.13 (1H, m), 2.83 (1H, m), 2.62 (1H, m)2.34 (3H, s), 1.21 (3H, t, J=7.2 Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 164A and 164B, which had identical spectral data.

Example 165N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

A solution of Preparation A (0.18 g, 0.80 mmol), Preparation AHc (0.30g, 0.89 mmol), Na₂CO₃ (0.190 g, 1.79 mmol) and xantphos (0.519 g, 0.89mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.465 g, 0.440 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diamataceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (20 mL×3). The combined organic layer waswashed with brine solution (25 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (0.5% aqueous ammonium acetate inmethanol) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(0.13 g, 28%) as off-brown solid. LC-MS (M+H)⁺=522.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.13 (1H, s), 7.86 (1H, s), 7.73 (1H, s), 7.42 (1H, s),7.24 (2H, m), 7.15-7.07 (4H, m), 4.13 (1H, m), 3.55 (3H, s), 3.47-3.41(4H, m), 3.04 (3H, s), 2.99 (1H, m), 2.48 (1H, m), 2.34 (3H, s), 1.23(3H, t, J=7.2 Hz).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 165A and 165B, which had identical spectral data.

Example 166N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

This example is the same compound as Preparation All (vide supra).

Example 167N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

A solution of Preparation A (0.190 g, 0.851 mmol), Preparation AId (0.40g, 0.851 mmol), Na₂CO₃ (0.180 g, 1.70 mmol) and xantphos (0.491 g, 0.851mmol) in dioxane/water (9:1) was purged with argon for 1 h at roomtemperature. Pd(dba)₃ (0.440 g, 0.425 mmol) was added to the reactionmixture and the resulting solution was purged with argon for another 1h. The reaction mass was heated at 110° C. for 24 h. The reaction masswas filtered through a bed of diamataceous earth (Celite®) and washedwith ethyl acetate. The filtrate was evaporated under reduced pressureand the residue was diluted with water. The aqueous solution wasextracted with ethyl acetate (25 mL×3). The combined organic layer waswashed with brine solution (20 mL), dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to get crude compound. The crudecompound was purified by column chromatography (60-120 mesh) using 50%ethyl acetate in pet-ether as mobile phase to give a mixture of twodiasteriomersN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine(0.40 g, 88%, crude) as off-white solid. LC-MS (M+H)⁺=658.2. ¹H NMR (400MHz, DMSO-d6): δ ppm 8.95 (1H, s), 7.75 (1H, s), 7.74 (1H, s), 7.54 (2H,m), 7.43 (1H, s), 7.29 (1H, m), 7.22-7.14 (5H, m), 6.86 (2H, m), 5.34(1H, m), 4.38 (1H, s), 4.03 (1H, m), 4.0 (3H, m), 3.72 (6H, s), 3.51(1H, m), 3.33 (1H, m), 2.95 (2H, m), 2.51 (1H, m), 2.25-2.01 (3H, m).

The diasteriomeric mixture was separated by chiral chromatography toafford two diasteriomers Example 167A and 167B.

Example 168N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

To a solution of Preparation AIk (0.06 g, 0.121 mmol) in dichloromethanewas added diisopropylethylamine (0.041 g, 0.243 mmol) at −10° C.followed by methanesulfonyl chloride (0.013 g, 0.121 mmol). The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with dichloromethane, washed with water, evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine(0.020 g, 29%) as off-white solid. LC-MS (M+H)⁺=572.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.23 (1H, s), 7.97 (1H, s), 7.74 (1H, s), 7.43 (1H, s),7.35 (2H, m), 7.23-7.12 (4H, m), 7.0 (1H, m), 5.57 (1H, s), 3.85 (1H,m), 3.79 (3H, s), 3.54 (2H, m), 3.18 (1H, m), 2.88 (3H, s), 2.65 (2H,m), 1.24 (3H, t, J=7.2 Hz).

The racemic mixture was separated by chiral chromatography to afford twoenantiomers Example 168A and 168B.

Example 169N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,7-diethyl-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

To a solution of Preparation AIk (0.20 g, 0.405 mmol) in dichloromethanewas added diisopropylethylamine (0.104 g, 0.806 mmol) at −10° C.followed by ethyl iodide (0.31 g, 0.231 mmol). The reaction mixture wasstirred at room temperature for 1 h. The reaction mixture was dilutedwith dichloromethane, washed with water, evaporated under reducedpressure to get crude compound. The crude compound was purified byprep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,7-diethyl-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine(0.110 g, 62%) as off-white solid. LC-MS (M-FH)⁺=522.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 8.90 (1H, s), 7.70 (1H, s), 7.73 (1H, s), 7.42 (1H, s),7.28 (2H, m), 7.17 (4H, m), 6.78 (1H, m), 4.39 (1H, s), 3.65 (3H, s),3.48 (2H, m), 3.13 (2H, m), 3.08 (1H, m), 2.51 (1H, m), 2.39 (2H, m),1.22-1.19 (6H, m).

The racemic mixture was separated by chiral chromatography to afford twoenantiomers Example 169A and 169B.

Example 170 methyl2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-(4-fluorophenyl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a solution of Preparation of AIk (0.10 g, 0.20 mmol) indichloromethane was added triethylamine (0.019 g, 0.20 mmol) at −10° C.followed by methyl chloroformate (0.18 g, 0.20 mmol). The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with dichloromethane, washed with water, evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to givemethyl2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-(4-fluorophenyl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(0.080 g, 76%) as off-white solid. LC-MS (M+H)⁺=552.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.22 (1H, s), 7.96 (1H, s), 7.74 (1H, s), 7.48 (1H, s),7.33 (2H, m), 7.20-7.13 (4H, m), 6.98 (1H, m), 4.06 (1H, s), 3.82 (1H,m), 3.75 (3H, s), 3.68 (3H, s), 3.56 (2H, m), 3.02 (1H, m), 2.33 (2H,m), 1.21 (3H, t, J=7.2 Hz).

The racemic mixture was separated by chiral chromatography to afford twoenantiomers Example 170A and 170B.

Example 1711-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-(4-fluorophenyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethanone

To a solution of Preparation AIk (0.052 g, 0.101 mmol) indichloromethane was added triethylamine (0.012 g, 0.126 mmol) at −10° C.followed by acetyl chloride (0.007 g, 0.01 mmol). The reaction mixturewas stirred at room temperature for 1 h. The reaction mixture wasdiluted with dichloromethane, washed with water, evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to give1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-(4-fluorophenyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethanone(0.040 g, 72%) as off-white solid. LC-MS (M+H)⁺=536.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.25 (1H, s), 8.0 (1H, s), 7.75 (1H, s), 7.43 (1H, s),7.32 (2H, m), 7.21-7.14 (4H, m), 6.99 (1H, m), 6.36 (1H, sb), 3.95 (1H,m), 3.90 (2H, m), 3.57 (3H, s), 3.49 (1H, m), 3.20 (1H, m), 2.34 (1H,m), 2.12 (3H, s), 1.22 (3H, t, J=7.2 Hz).

Example 172N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

To a solution of Preparation AB (0.070 g, 0.138 mmol) in dichloromethanewas added diisopropylethylamine (0.047 g, 0.276 mmol) at −10° C.followed by methanesulfonyl chloride (0.015 g, 0.138 mmol). The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with dichloromethane, washed with water, evaporated underreduced pressure to get crude compound. The crude compound was purifiedby prep-HPLC (aqueous 0.1% ammonium acetate in acetonitrile) to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine(0.030 g, 37%) as off-white solid. LC-MS (M+H)⁺=586.2. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.26 (1H, s), 7.80 (1H, s), 7.74 (1H, s), 7.43 (1H, s),7.34 (2H, m), 7.32-7.16 (4H, m), 5.65 (1H, s), 3.55 (1H, m), 3.53 (3H,s), 3.51 (2H, m), 3.18 (1H, m), 3.08 (3H, s), 2.91 (3H, s), 2.67 (1H,m), 1.22 (3H, m).

The racemic mixture was separated by chiral chromatography to afford twoenantiomers Example 172A and 172B.

Example 173N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-(R)-3-fluoropyrrolidin-1-yl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

To a solution of Preparation AIm (0.041 g, 0.074 mmol) indichloromethane was added diisopropylethylamine (0.019 g, 0.148 mmol) at−10° C. followed by addition of methanesulfonyl chloride (0.008 g, 0.074mmol). The reaction mixture was stirred at room temperature for 1 h. Thereaction mixture was diluted with dichloromethane, washed with water,evaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (aqueous 0.1% ammonium acetate inacetonitrile) toN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine(0.010 g, 20%) as off-white solid. LC-MS (M+H)⁺=616.0. ¹H NMR (400 MHz,DMSO-d6): δ ppm 9.27 (1H, s), 7.84 (1H, s), 7.75 (1H, s), 7.43 (1H, s),7.38 (2H, m), 7.22-7.17 (4H, m), 5.50 (1H, s), 4.11 (1H, m), 4.04 (3H,m), 3.82 (1H, m), 3.51 (3H, s), 3.23 (2H, m), 3.05 (2H, m), 2.95 (3H,s), 2.23 (2H, m).

Example 174N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-(R)-3-fluoropyrrolidin-1-yl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

To a solution of Preparation AIn (0.041 g, 0.074 mmol) indichloromethane was added diisopropylethylamine (0.019 g, 0.148 mmol) at−10° C. followed by addition of methanesulfonyl chloride (0.008 g, 0.074mmol). The reaction mixture was stirred at room temperature for 1 h. Thereaction mixture was diluted with dichloromethane, washed with water,evaporated under reduced pressure to get crude compound. The crudecompound was purified by prep-HPLC (aqueous 0.1% ammonium acetate inacetonitrile) toN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine(0.012 g, 20.6%) as off-white solid. LC-MS (M+H)⁺=616.0. ¹H NMR (400MHz, DMSO-d6): δ ppm 9.25 (1H, s), 7.83 (1H, s), 7.74 (1H, s), 7.42 (1H,s), 7.33 (2H, m), 7.22-7.12 (4H, m), 5.76 (1H, s), 5.57 (1H, m), 4.07(1H, m), 3.99-3.90 (3H, m), 3.88 (1H, m), 3.54 (3H, s), 3.27 (1H, m),3.11 (1H, m), 2.93 (3H, s), 2.85 (1H, m), 2.23 (2H, m).

Example 175N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

Preparation AIk was combined with methyl iodide in the manner of Example169 to giveN2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

Example 176N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A solution of2-chloro-N-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(121.2 mg, 0.461 mmol) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (103 mg, 0.461 mmol) inTHF (1 mL) and acetic acid (1.000 mL) was heated at 80° C. overnight.The reaction mixture was purified by a reverse-phase preparative HPLCmethod to giveN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA salt (114.3 mg, 43%) as brown solid. LC-MS (M+H)⁺=450.0. ¹H NMR (500MHz, CDCl₃) δ ppm 8.86 (1H, s), 7.88 (1H, t, J=8.4 Hz), 7.22-7.31 (4H,m), 7.19 (1H, d, J=8.9 Hz), 7.07 (3H, t, J=8.7 Hz), 4.27 (1H, t, J=8.5Hz), 3.73 (3H, s), 2.45-2.59 (1H, m), 2.38 (1H, d, J=7.6 Hz), 2.30 (1H,d, J=3.7 Hz), 1.95-2.06 (1H, m).

Examples 176A and 176B(S)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)—N²-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture ofN²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(133 mg, 0.206 mmol from Example 176) was purified using chiralsupercritical fluid chromatography (SFC) to afford 28.4 mg of peak A(Example 176A) and 27.4 mg of peak B (Example 176B). SFC Method:Chiralpak OJ-H (30×250 mm, 5 μM), 40% methanol (0.1% diethylamine) inCO₂, 35° C., flow rate 70 mL/min for 16 min, absorbance 268 nm,injection 1 mL of 22 mg/mL solution in methanol (multiple stackedinjections), t_(R) (peak A)=5.0 min, t_(R) (peak B) 11.2 min. Theabsolute stereochemistry of individual enantiomers (Examples 176A and176B) was not determined LC-MS and ¹H NMR analytical data for theseparated enantiomers was identical to the racemate (Example 176).

Example 1772-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-8-phenyl-7,8-dihydroquinazolin-8-ol

A solution of2-chloro-4-(methylamino)-8-phenyl-7,8-dihydroquinazolin-8-ol (25 mg) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (29 mg) in dioxane (0.2mL) and acetic acid (0.2 mL) was heated at 85° C. for 4 h. THF wasremoved in vacuo, and the residue was purified by reverse phasepreparative to give the title compound (as its TFA salt) as an oil (18mg). LC-MS (M+H)⁺=475.26. ¹H NMR (TFA salt, 500 MHz, CD₃OD) δ ppm7.2-7.9 (m), 6.56 (1H, m), 6.18 (1H, m), 3.94 (3H, s), 3.20 (3H, s),3.10 (2H, m).

Example 1782-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-8-phenyl-5,6,7,8-tetrahydroquinazolin-8-ol

The title compound as its TFA salt form was made in the same fashion asdescribed in Example 177. LC-MS (M+H)⁺=477.28. ¹H NMR (TFA salt, 500MHz, CD₃OD) δ ppm 7.1-8.0 (m), 3.88 (3H, s), 3.18 (3H, s), 1.2-2.5 (6H,m).

Example 1792-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol

The mixture of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (37.1 mg,0.166 mmol),2-chloro-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol(40 mg, 0.138 mmol), Pd₂(dba)₃ (5.06 mg, 5.52 mmol), xanphos (7.99 mg,0.014 mmol) and Cs₂CO₃ (135 mg, 0.414 mmol) was heated at 100° C.overnight. The crude product was purified by Prep-HPLC (Column:PHENOMENEX LUNA C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5H2O/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 H2O/ACN. Flow rate: 40ml/min, 35-100% B, 30 min) to give the title compound as its TFA salt(32 mg). LC-MS (M+H)⁺=477.19. ¹H NMR (TFA salt, 500 MHz, CD₃OD) δ ppm6.8-7.8 (m), 3.64 (3H, s), 3.30 (6H, s), 3.0-3.2 (2H, m), and 2.4 (2H,m).

Example 180(6S,7S)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-6-ol

The reaction was carried out in the same fashion as described in Example177, but the purification method is different. The crude product waspurified by preparative TLC eluting with 50% acetone/hexanes to give thetitle compound as an oil. LC-MS (M+H)⁺=477.13. ¹H NMR (500 MHz, CDCl₃) δppm 6.8-7.9 (m), 4.48 (1H, m), 4.07 (1H, m), 3.58 (1H, m), 3.50 (3H, s),3.28 (6H, s), 3.12 (1H, m).

Example 181N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-chloroazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

In a manner similar to that described in Example 8, Preparation A andPreparation Gi were reacted to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-chloroazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine.LC-MS (M+H)⁺=507.2. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.71 (d,J=19.84 Hz, 1H) 8.50 (d, J=1.53 Hz, 1H) 7.45 (dd, J=8.85, 1.83 Hz, 1H)7.24-7.40 (m, 5H) 7.18-7.23 (m, 2H) 5.12 (br. s., 1H) 4.76-4.95 (m, 2H)4.71 (d, J=10.68 Hz, 1H) 4.35-4.54 (m, 2H) 3.88 (s, 3H) 3.12 (d, J=14.65Hz, 1H) 3.01 (dd, J=19.99, 6.26 Hz, 1H) 2.68-2.85 (m, 1H) 2.24-2.42 (m,1H).

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 181A and 181B.

Example 182N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-fluoroazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

In a manner similar to that described in Example 8, Preparation A andPreparation Gj were reacted to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-fluoroazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine.LC-MS (M+H)⁺=491.2. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.07 (br. s.,1H) 8.30 (br. s., 1H) 7.45 (d, J=8.55 Hz, 2H) 7.38 (br. s., 3H) 7.33 (d,J=4.88 Hz, 2H) 7.13-7.31 (m, 1H) 5.50-5.61 (m, 1H) 4.91 (br. s., 1H)4.71 (br. s., 2H) 4.43 (br. s., 2H) 3.89 (br. s., 3H) 3.14 (br. s., 1H)3.03 (d, J=18.92 Hz, 1H) 2.75 (br. s., 1H) 2.20-2.39 (m, 1H).

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 182A and 182B.

Example 183N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-methoxyazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

In a manner similar to that described in Example 8, Preparation A andPreparation Gk were reacted to giveN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-methoxyazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine.LC-MS (M+H)⁺=503.2. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.73 (1H, br.s.), 7.49 (1H, s), 7.30-7.35 (2H, m), 7.22 (4H, t, J=8.24 Hz), 7.04-7.07(1H, m), 7.00 (1H, s), 6.90 (1H, br. s.), 4.45-4.52 (2H, m), 4.33-4.39(1H, m), 4.16-4.23 (3H, m), 3.57 (3H, s), 2.98-3.07 (1H, m), 2.85-2.96(1H, m), 2.55-2.67 (1H, m, J=13.28, 8.77, 8.77, 4.58 Hz), 2.06-2.16 (1H,m).

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 183A and 183B.

Example 184N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

The mixture of2-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,8-dioxa-2-azaspiro[3.4]octane(Preparation Gl) (23 mg, 0.067 mmol),4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (17.95mg, 0.080 mmol), Tris(dibenzylidineacetone)dipalladium(0) (3.06 mg, 3.34μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.87mg, 6.69 μmol) and sodium carbonate (14.18 mg, 0.134 mmol) in Dioxane(319 μL)/Water (63.7 μL) was heated at 100° C. overnight. The crudeproduct was purified by Prep-HPLC (Solvent A=10% MeOH-90% H2O-0.1% TFA,Solvent B=90% MeOH-10% H2O-0.1% TFA. Column. PHENOMENEX LUNA 30×100 mm,S10, Flow rate: 40 ml/min, 30-100% B, 30 min) to obtainN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (17 mg, 0.024 mmol, 35.5% yield).

LC-MS (M+H)⁺=531.1 ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.39 (s, 1H)8.09 (s, 1H) 7.45 (d, J=8.55 Hz, 1H) 7.35-7.42 (m, 4H) 7.19-7.34 (m, 1H)7.15 (s, 2 H) 4.73 (br. s., 2H) 4.51 (br. s., 2H) 4.42 (dd, J=8.70, 4.12Hz, 1H) 4.09 (d, J=3.66 Hz, 4H) 3.87 (s, 3H) 3.12 (dd, J=14.34, 7.02 Hz,1H) 2.90-3.05 (m, 1H) 2.67-2.81 (m, 1 H) 2.29 (ddd, J=9.16, 4.43, 4.12Hz, 1H).

Example 1851-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one

The mixture ofN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 184) (12 mg, 0.023 mmol) in Acetone (161 μL)/Water (32.3μL)/HClO4, 70% (32.3 μL) was heated at 50° C. overnight. The crudeproduct was purified by Prep-HPLC to get1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one(2.5 mg, 4.62 μmol, 20.5% yield). LC-MS (M+H)⁺=487.2 ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 7.57 (s, 1H) 7.42 (t, J=7.63 Hz, 3H) 7.26-7.38 (m,3H) 7.12-7.26 (m, 2H) 7.00-7.12 (m, 1H) 5.23 (br. s., 4H) 4.43 (br. s.,1H) 3.68-3.79 (m, 3H) 3.10-3.27 (m, 1H) 2.93-3.08 (m, 1H) 2.71-2.84 (m,1H) 2.37 (br. s., 1H).

Example 1861-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylazetidine-3-carbonitrile

In a manner similar to that described in Example 184, Preparation Hacand Preparation A were combined to obtain1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylazetidine-3-carbonitrile.LC-MS (M+H)⁺=530.1 ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.50 (br. s.,1H) 8.18 (br. s., 1H) 7.46 (d, J=7.63 Hz, 1H) 7.12-7.31 (m, 3H) 7.06(br. s., 3H) 4.99 (br. s., 1H) 4.72 (br. s., 1H) 4.43 (br. s., 2H) 4.28(br. s., 1H) 3.88 (s, 3H) 3.11 (br. s., 1H) 3.00 (br. s., 1H) 2.76 (br.s., 1H) 2.28 (d, J=5.49 Hz, 1H) 1.87 (s, 3H).

Example 187N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-ethoxyazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

In a manner similar to that described in Example 184, Preparation Hadand Preparation A were combined to obtainN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-ethoxyazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine.LC-MS (M+H)⁺=535.1 ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.77 (br. s.,1H) 7.74 (d, J=4.58 Hz, 1H) 7.52 (br. s., 1H) 7.34-7.41 (m, 1H)7.12-7.30 (m, 2H) 7.06-7.12 (m, 1H) 7.03 (br. s., 2H) 4.77 (br. s., 1H)4.51 (br. s., 2H) 4.49 (d, J=5.49 Hz, 1H) 4.36 (br. s., 1H) 4.24 (br.s., 1H) 3.85 (d, J=4.88 Hz, 3H) 3.55 (dd, J=6.71, 5.49 Hz, 2H) 3.12 (br.s., 1H) 2.99 (br. s., 1H) 2.68 (br. s., 1H) 2.23 (br. s., 1H) 1.21-1.37(m, 3H).

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 187A and 187B.

Example 188N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(5-oxa-2-azaspiro[3.4]octan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

In a manner similar to that described in Example 184, Preparation Gm andPreparation A were combined to obtainN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(5-oxa-2-azaspiro[3.4]octan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine.LC-MS (M+H)⁺=529.3 ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.85 (br. s.,1H) 8.36 (br. s., 1H) 7.49 (br. s., 4H) 7.20-7.39 (m, 4H) 4.56 (d,J=9.16 Hz, 1H) 4.41 (br. s., 3H) 3.92-4.10 (m, 3H) 3.87 (s, 3H) 3.11(br. s., 1H) 3.00 (d, J=12.51 Hz, 1H) 2.73 (br. s., 1H) 2.26 (t, J=6.87Hz, 3H) 2.06 (d, J=6.41 Hz, 2H).

Example 1891-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylazetidin-3-ol

In a manner similar to that described in Example 184, Preparation Haeand Preparation A were combined to obtain1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylazetidin-3-ol.LC-MS (M+H)⁺=521.1 ¹H NMR (400 MHz, MeOD) δ ppm 7.93 (d, J=1.51 Hz, 1H)7.65 (d, J=2.26 Hz, 1H) 7.26-7.44 (m, 4H) 7.01-7.26 (m, 4 H) 4.48-4.68(m, 2H) 4.44 (dd, J=9.03, 6.78 Hz, 1H) 4.18-4.38 (m, 2H) 3.90 (s, 3H)3.15 (dd, J=5.27, 3.76 Hz, 1H) 2.96-3.06 (m, 1H) 2.62-2.82 (m, 1H) 2.12(dddd, J=13.18, 8.85, 6.46, 6.15 Hz, 1H) 1.55-1.66 (m, 3H).

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 189A and 189B.

Example 190N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-fluoro-3-methylazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

A solution of1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylazetidin-3-ol(35 mg, 0.067 mmol) in CH₂Cl₂ (Volume: 274 μl) was cooled to −78° C. Tothis mixture was added [Bis(2-methoxyethyl)amino]sulfur trifluoride(13.62 μl, 0.074 mmol) dropwise and the solution was stirred for 30 minsat −78° C. and then warmed to 0° C. and stirred for a further 1 hr.Reaction was quenched with Sat. NaHCO₃ solution and brine. The aqueouslayer was extracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄and concentrated. The crude product was purified by Prep-HPLC to obtainN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-fluoro-3-methylazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine,TFA (4.0 mg, 5.65 μmol). LC-MS (M+H)⁺=523.1 ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 11.38 (br. s., 1H) 8.14 (s, 1H) 7.43-7.54 (m, 1H)7.30-7.38 (m, 1H) 7.20-7.26 (m, 3H) 7.16 (s, 1H) 7.06 (t, J=7.78 Hz, 2H)4.78 (br. s., 1H) 4.54 (br. s., 2H) 4.42 (br. s., 2H) 3.88 (s, 3H) 3.12(d, J=7.93 Hz, 1H) 3.00 (br. s., 1H) 2.75 (br. s., 1H) 2.21-2.34 (m, 1H) 1.78-1.82 (br. s, 3H).

Example 191N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-methoxy-3-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

In a manner similar to that described in Example 184, Preparation Hafand Preparation A were combined to obtainN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-methoxy-3-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine.LC-MS (M+H)⁺=535.1 ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.75 (d, J=4.27Hz, 1H) 7.83 (d, J=1.22 Hz, 1H) 7.47 (d, J=1.83 Hz, 1H) 7.44 (d, J=8.55Hz, 1H) 7.15-7.33 (m, 4H) 7.03 (t, J=7.63 Hz, 2H) 4.53 (d, J=8.85 Hz,1H) 4.24-4.43 (m, 3H) 4.06-4.19 (m, 1H) 3.86 (s, 3H) 3.34 (s, 3 H) 3.13(ddd, J=12.67, 6.56, 6.41 Hz, 1H) 3.01 (ddd, J=15.95, 4.81, 4.58 Hz, 1H)2.70 (td, J=9.46, 3.66 Hz, 1H) 2.24 (tt, J=8.96, 4.31 Hz, 1H) 1.63 (s,3H).

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 191A and 191B.

Example 1927-(4-fluorophenyl)-4-(3-methoxy-3-methylazetidin-1-yl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

In a manner similar to that described in Example 184, Preparation Hafand Preparation D were combined to obtain7-(4-fluorophenyl)-4-(3-methoxy-3-methylazetidin-1-yl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine.LC-MS (M+H)⁺=516.1 ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.77 (d, J=3.97Hz, 1H) 8.88 (s, 1H) 7.69 (d, J=8.55 Hz, 1H) 7.52 (dd, J=8.85, 2.14 Hz,1H) 7.47 (s, 1H) 7.23 (t, J=5.49 Hz, 2H) 7.03 (t, J=8.39 Hz, 2H)4.45-4.58 (m, 1H) 4.35 (d, J=4.58 Hz, 2H) 4.27 (d, J=7.63 Hz, 1H) 4.10(d, J=10.07 Hz, 1H) 3.85-4.04 (m, 3H) 3.33 (s, 3H) 3.05-3.20 (m, 1H)2.92-3.05 (m, 1H) 2.63-2.79 (m, 1H) 2.45-2.59 (m, 3H) 2.23 (td, J=8.39,4.27 Hz, 1H) 1.57-1.72 (m, 3H).

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 192A and 192B.

Example 1937-(2,4-difluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The mixture of2-chloro-7-(2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(153 mg, 0.517 mmol),3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (211 mg, 1.035 mmol)and H₂SO₄ (44.1 μl, 0.828 mmol) in N-Methyl-2-pyrrolidinone (Volume:2070 μl) was heated at 100° C. overnight. Added Sat.NaHCO₃ slowly, andextracted with EtOAc (×3). The combined organic layer was dried overNa₂SO₄ and concentrated. The crude product was purified by Prep-HPLC(Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1%TFA. Column. PHENOMENEX LUNA 30×100 mm, S10, Flow rate: 40 ml/min,30-100% B, 15 min) to get7-(2,4-difluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,TFA (287 mg, 0.447 mmol, 86% yield). LC-MS (M+H)⁺=464.1. ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 11.54 (1H, s), 9.22 (1H, s), 7.75 (1H, d,J=8.85 Hz), 7.65 (1H, s), 7.49 (1H, d, J=8.85 Hz), 7.13-7.21 (1H, m),6.79-6.91 (2H, m), 6.11 (1H, d, J=4.27 Hz), 4.56-4.63 (1H, m), 3.97 (3H,s), 3.23 (3H, d, J=4.27 Hz), 2.84-2.93 (1H, m), 2.71-2.81 (2H, m), 2.62(3H, s), 2.19-2.28 (1H, m).

Examples 193A and 193B(S)-7-(2,4-difluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineand(R)-7-(2,4-difluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

A racemic mixture of7-(2,4-difluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(Example 193) was purified using chiral supercritical fluidchromatography (SFC) to afford peak A (Example 193A) and peak B (Example193B). SFC Method: Chiralpak OJ-H (30×150 mm), 30% methanol (0.1%diethylamine) in CO₂, 100 bar, flow rate 50 mL/min for 12 min,absorbance 268 nm, injection 2.0 mL of 10 mg/mL solution in methanol,t_(R) (peak A)=4.7 min, t_(R) (peak B) 9.6 min. The absolutestereochemistry of individual enantiomers (Examples 193A and 193B) wasnot determined 193A: LC-MS (M+H)⁺=446.2. LC R_(t) 13.03 min (WatersSunfire 4.6×150 mm 10 to 100% B in A over 15 min, 1.5 mL/min. (A is90:10:0.1 water:MeOH:TFA; B is 90:10:0.1 MeOH:water:TFA)). ¹H NMR (500MHz, CHLOROFORM-d) δ ppm 8.46 (1H, s), 8.04 (1H, s), 7.51 (1H, d, J=8.55Hz), 7.04-7.13 (2H, m), 6.78-6.87 (3H, m), 4.42-4.50 (1H, m), 3.68 (3H,s), 3.13 (3H, s), 2.62-2.79 (3H, m), 2.49 (3H, s), 1.96-2.08 (1H, m).

Example 1946-(2,2-difluoroethyl)-N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

Preparation AEo was reacted with difluoro-2-iodoethane, potassiumcarbonate, and sodium iodide in DMF at 80° C. to afford6-(2,2-difluoroethyl)-N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(Example 194). LC-MS (M+H)⁺=509.4.

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 194A and 194B.

Example 1956-(2,2-difluoroethyl)-N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

Preparation AEm was reacted with difluoro-2-iodoethane, potassiumcarbonate, and sodium iodide in DMF at 80° C. to afford6-(2,2-difluoroethyl)-N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(Example 195). LC-MS (M+H)⁺=509.2.

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 195A and 195B.

Example 196N4-ethyl-N2-(3-methoxy-4-(4-chloro-1H-13-imidazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

In a manner similar to Preparation AEp and Example 146, Preparation AEkwas transformed intoN4-ethyl-N2-(3-methoxy-4-(4-chloro-1H-13-imidazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(Example 196). LC-MS (M+H)⁺=558.2.

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 196A and 196B.

Example 197N4-ethyl-N2-(3-methoxy-4-(4-chloro-1H-13-imidazol-1-yl)phenyl)-8-phenyl-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

Preparation AEk was reacted with difluoro-2-iodoethane, potassiumcarbonate, and sodium iodide in DMF at 80° C. to affordN4-ethyl-N2-(3-methoxy-4-(4-chloro-1H-13-imidazol-1-yl)phenyl)-8-phenyl-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine(Example 197). LC-MS (M+H)⁺=540.2.

The individual enantiomers were separated by chiral SFC chromatographyto yield examples 197A and 197B.

Example 1988-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

In a manner similar to that described in Example 8, Preparation D andPreparation AHa were reacted to give8-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine.LC-MS (M+H)⁺=475.2. The racemic mixture was separated by chiralchromatography to afford the enantiomers Example 198A and 198B.

Example 1998-(4-fluorophenyl)-N2-(3-methoxy-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

In a manner similar to that described in Example 8, Preparation DD andPreparation AHa were reacted to give8-(4-fluorophenyl)-N2-(3-methoxy-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine.LC-MS (M+H)⁺=475.2.

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 199A and 199B.

Example 200(±)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one

A solution of2-chloro-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one(Preparation AN) (7 mg) and4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (7 mg) inTHF (0.2 mL) and sulfuric acid (4 mg) was heated at 85° C. for 12 h. THFwas removed in vacuo, and the residue was purified by reverse phasepreparative to give the title compound (as its TFA salt) as a yellowishoil (9 mg). LC-MS (M+H)⁺=461.12. ¹H NMR (500 MHz, CD₃OD) δ ppm 7.80 (m),7.1-7.4 (m), 4.50 (1H, m), 3.25 (1H, m), 2.56 (1H, m), 3.50 (3H, s), and3.19 (3H, s).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 200A and 200B.

Example 201(E)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-oneO-methyl oxime

A 0.15M solution of Example 200 in iPrOH was heated with 4 eqmethoxyamine hydrochloride at 85° C. for 3 h. Reverse-phase HPLCprovided the desired material as a TFA salt. LC-MS (M+H)⁺=490.2.

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 201A and 201B.

Example 2022-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-ol

To a solution of Example 201 in methanol at rt was added NaBH₄, and ther×n mixture was stirred at rt for 1 h. The r×n was worked up withEtOAc/H₂O to give the desired pdt as a white solid. LC-MS (M+H)⁺=463.1.

Example 203N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine

LC-MS (M+H)⁺=466.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86 (1H, d,J=2.3 Hz), 7.48 (1H, d, J=1.5 Hz), 7.24-7.32 (4H, m), 7.16-7.23 (1H, m),7.08-7.14 (2H, m), 7.00 (2H, s), 6.70 (1H, dd, J=8.3, 2.0 Hz), 4.71 (1H,d, J=3.0 Hz), 4.03 (1H, t, J=5.6 Hz), 3.41 (3H, s), 3.12 (3H, d, J=4.8Hz), 2.30-2.48 (2H, m), 2.09-2.22 (1H, m, J=13.0, 9.7, 6.2, 3.3, 3.1Hz), 1.74-1.96 (3H, m).

The racemic mixture was separated by chiral chromatography to afford theenantiomers Example 203A and 203B.

Example 2041-(2-methoxy-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)-1H-imidazole-4-carbonitrile

To a solution of2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Ga) (150 mg, 0.578 mmol) in Dioxane (Ratio: 1, Volume: 1013μl) was added 1-(4-amino-2-methoxyphenyl)-1H-imidazole-4-carbonitrile(Preparation AA) (124 mg, 0.578 mmol), and AcOH (Ratio: 1.000, Volume:1013 μl). The resulting mixture was brought to 100° C. in a sealed vialand stirred overnight. The mixture was brought to pH 8 by the additionof 1 N aqueous sodium Hydroxide. The resulting mixture was extractedwith EtOAc (3×1 mL). The combined extracts were dried over MgSO₄,filtered and concentrated in vacuo. Purification by prep HPLC (WatersSunfire C18, 50×250 mm, acetonitrile/H₂O/ammonium acetate) gave1-(2-methoxy-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)-1H-imidazole-4-carbonitrile(57 mg, 0.130 mmol, 22.56% yield). LC-MS (M+H)⁺=438.2. ¹H NMR (500 MHz,MeOD) δ ppm 8.02-8.08 (2H, m), 7.90-7.94 (1H, m), 7.31 (2H, t, J=7.63Hz), 7.16-7.24 (4H, m), 6.99 (1H, dd, J=8.55, 2.14 Hz), 4.18 (1H, t,J=8.09 Hz), 3.56 (3H, s), 3.07 (3H, s), 2.76-2.84 (1H, m), 2.59-2.74(2H, m), 1.98-2.05 (1H, m). The racemic mixture was separated by chiralchromatography to afford the enantiomers Example 204A and 204B.

Example 205N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

In a manner similar to that described in Example 184, Preparation Go andPreparation A were combined to obtainN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine.LC-MS (M+H)⁺=545.1. 1H NMR (500 MHz, MeOD) δ ppm 7.89 (1H, s), 7.62(0.5H, br. s.), 7.53 (0.5H, br. s.), 7.37-7.45 (4H, m), 7.32-7.36 (1H,m), 7.30 (2H, d, J=7.63 Hz), 7.23 (0.5H, d, J=7.63 Hz), 7.14 (0.5H, d,J=7.32 Hz), 4.40-4.47 (1H, m), 4.25 (1H, br. s.), 3.96-4.14 (6H, m),3.88 (4H, br. s.), 3.34-3.46 (1H, m), 3.28 (1H, br. s.), 2.69-2.79 (1H,m), 2.24-2.32 (1H, m), 2.09-2.23 (2H, m).

Example 2061-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-one

The mixture ofN-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(Example 205) (37 mg, 0.068 mmol) and HCl (272 μL, 0.272 mmol) in THF(339 μL) was heated at 60° C. overnight. Concentrated to remove THF andadded Acetone (339 μL) and HCl (272 μL, 0.272 mmol) to the mixture. Themixture was heated at 60° C. for 6 h. The crude product was purified byPrep-HPLC (Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10%H2O-0.1% TFA. Column. PHENOMENEX LUNA 30×100 mm, S10, Flow rate: 40ml/min, 35-100% B, 40 min) and then was purified by Prep-HPLC (Column:PHENOMENEX LUNA C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5H2O/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 H2O/ACN. Flow rate: 40ml/min, 30-100% B, 35 min) to get1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-one(2.0 mg, 3.59 μmol, 5.29% yield).

LC-MS (M+H)⁺=501.3.

Example 2074-(8-(4-fluorophenyl)-4-(methylamino)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)benzonitrile

Utilizing 4-aminobenzonitrile and Preparation AGa successively by thegeneral methods described in Preparation AGj, AGk, and AGp, the titlecompound was obtained. LC-MS (M+H)⁺=453.2. ¹H NMR (400 MHz, DMSO-d) δppm 9.25 (s, 1H) 7.85 (d, J=8.80 Hz, 2H) 7.55 (d, J=8.80 Hz, 2H)7.25-7.29 (m, 2H) 7.10-7.17 (m, 3H) 4.05-4.24 (m, 3H) 3.53-3.63 (m, 2H)2.95 (d, J=4.4 Hz, 3H) 2.95 (s, 3H).

Example 208N2-(4-(4-(difluoromethyl)-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

In a manner similar to that described in Example 8, Preparation EE andPreparation Hh were reacted to giveN2-(4-(4-(difluoromethyl)-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine.LC-MS (M+H)⁺=481.1 ¹H NMR (500 MHz, MeOD) δ ppm 8.19 (s, 1H) 7.75 (br.s., 1H) 7.71 (s, 1H) 7.45 (dd, J=8.55, 3.05 Hz, 1H) 7.31 (ddd, J=8.47,5.26, 2.75 Hz, 2H) 7.19-7.26 (m, 1H) 7.15 (td, J=8.77, 2.90 Hz, 2 H)6.83 (t, J=55 Hz, 1H) 4.51 (d, J=2.75 Hz, 1H) 3.91 (d, J=3.05 Hz, 3H)3.18 (d, J=3.05 Hz, 3H) 2.92 (d, J=9.16 Hz, 1H) 2.76-2.85 (m, 2H)2.10-2.20 (m, 1H).

Example 209N2-(3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

In a manner similar to that described in Example 8, Preparation AO andPreparation Ga were reacted to giveN2-(3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamineLC-MS (M+H)⁺=425.4. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.84 (1H, d,J=2.01 Hz), 7.81 (1H, s), 7.74 (1H, s), 7.32 (3H, dd, J=13.55, 7.78 Hz),7.19-7.26 (3 H, m), 7.07 (1H, s), 6.78 (1H, dd, J=8.28, 2.01 Hz), 4.60(1H, q, J=4.52 Hz), 4.16-4.23 (1H, m), 3.91 (3H, s), 3.64 (3H, s), 3.11(3H, d, J=5.02 Hz), 2.58-2.76 (3H, m), 2.00-2.11 (1H, m).

Example 210N-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylmethanesulfonamide

Preparation G was reacted with 0.9 eq MeSO2NHMe, 0.1 eq Pd(OAc)2, 0.15eq xanphos and Cs2CO3 at 110° C. Preparation A was then added, resultingin the title compound. LC-MS (M+H)⁺=525.4 ¹H NMR (400 MHz, DMSO-d) δ ppm9.79 (s, 1H) 7.75-7.77 (m., 2H) 7.45 (s, 1H) 7.32-7.35 (m, 2H) 7.23-7.27(m, 4H) 7.16-7.18 (m, 1H) 4.35 (t, J=8.80 Hz, 1H) 3.40 (s, 3H) 3.31 (s,3H) 2.94-3.06 (m, 2H) 2.57-2.61 (m, 1H) 2.51 (s, 3H) 2.04-2.08 (m, 1H).

Example 211N-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methanesulfonamide

The title compound was prepared as for Example 210, substitutingMeSO2NH2. LC-MS (M+H)⁺=511.0 ¹H NMR (400 MHz, DMSO-d) δ ppm 9.51 (s, 1H)7.73-7.76 (m., 2 H) 7.41 (s, 1H) 7.16-7.31 (m, 8H) 4.21 (t, J=8.40 Hz,1H) 3.54 (s, 3H) 3.41 (s, 3H) 2.88-2.93 (m, 2H) 2.69-2.73 (m, 1H)1.91-1.97 (m, 1H).

Example 212N-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylacetamide

Intermediate Ga was reacted with p-methoxybenzylamine in the manner ofPreparation Gd. Coupling with Preparation A under the conditions ofExample 184, followed by treatment with TFA, led to the C4 NH₂ compound.Reaction with AcCl in dichloroethane and DIPEA at ambient temperaturefor 4 h yielded the named compound. LC-MS (M+H)⁺=489.2. ¹H NMR (400 MHz,DMSO-d) δ ppm 9.89 (s, 1H), 7.92 (s, 1H), 7.75 (s, 1H), 7.44 (s, 1H),7.36-7.12 (m, 7H), 4.38 (t, J=8.6 Hz, 1H), 3.51 (s, 3H), 3.33 (s, 3H),2.81 (t, J=7.4 Hz, 2H), 2.59-2.55 (m, 1H), 2.17 (s, 3H), 2.03 (dd,J=8.8, 12.4 Hz, 1H).

Example 213N-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-acetamide

To a solution of Intermediate Ga was added 1.5 eq AcCl and 2 eq DIPEAand allowed to reflux for 3 days. The product so-obtained was coupledwith Preparation A by the method of Example 184 to afford the titlecompound. LC-MS (M+H)⁺=475.2 ¹H NMR (400 MHz, DMSO-d) δ ppm 7.86 (s, 1H)7.54 (s., 1H) 7.35 (d, J=8.40 1H) 7.23-7.30 (m, 2H) 7.04-7.21 (m, 6H)6.73-6.76 (m, 1H) 4.26 (t, J=8.00 Hz, 1H) 3.71 (s, 3H) 2.58-2.80 (m, 3H)2.02 (s, 3H) 1.96-2.00 (m, 1H).

Example 214N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-(5-isopropyl-2-methylphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

To a solution of2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(Preparation Gp) (26.0 mg, 100 μmol) in Dioxane (Ratio: 1, Volume: 175μl) was added 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline(Preparation A) (22.37 mg, 100 μmol) and AcOH (Ratio: 1.000, Volume: 175μl). The resulting mixture was brought to 100° C. and stirred overnight.The reaction mixture was brought to pH 10 by the addition of 1 N aqueousNaOH. The resulting mixture was extracted with EtOAc (3×4 mL). Thecombined organic extracts were washed with brine (4 mL), dried overMgSO₄, filtered and concentrated in vacuo. The product was purified byPrep HPLC to yield the title compound. LC-MS (M+H)⁺=565.2.

Example 215A and 215B4-(4-(5-isopropyl-2-methylphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile

The method of Example 214 was used to combine 4-aminobenzonitrile andPreparation Gp to afford the title compounds as two distinct andseparable atropisomers. LC-MS (M+H)⁺=460.3.

Examples 216-256

The following general methods were used to join the appropriate anilinewith Preparation Ga.

Coupling Method A^(a): The method as described in Example 8.Coupling Method B^(a): The two components were heated at 100° C. in 1:1HOAc/Dioxane.

Analysis was conducted on one of the following columns^(b):

LC Method A^(b): Phenomenex Luna 3×50 95/5 to 5/95 water/MeOH, 0.1% TFALC Method B^(b): Phenomenex Luna 2×50 95/5 to 5/95 water/CH3CN, 0.1%NH4OAcLC Method C^(b): Phenomenex Luna 2×50 95/5 to 5/95 water/MeOH, 0.1% TFALC Method D^(b): Waters 2×50 95/5 to 5/95 water/MeOH, 0.1% NH4OAcLC Method E^(b): Supelco Ascentis Exp 95/5 to 5/95 water/CH3CN, 0.1%NH4OAcLC Retention Times^(c) are reported along with the gradient run time(rt/grt).

LC Coupling LC Retention Example Compound Name Method^(a) Method^(b)time^(c) (M + H)⁺ 216 N4-methyl-N2-(2- B A 1.77/3 332.2methylpyridin-4-yl)-7- phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine-2,4-diamine 217 N2-(3-methoxyphenyl)-N4- A D 3.63/4 347.2methyl-7-phenyl-6,7- dihydro-5H- cyclopenta[d]pyrimidine- 2,4-diamine218 N2-(4-fluorophenyl)-N4- A D 3.68/4 335.2 methyl-7-phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine- 2,4-diamine 219N2-(3,5-difluorophenyl)-N4- A D 3.87/4 353.2 methyl-7-phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine- 2,4-diamine 220 N2-(4-chloro-3- A D3.83/4 381.2 methoxyphenyl)-N4-methyl- 7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 221 N2-(4-bromo-2- A D 4.10/4 425.1methoxyphenyl)-N4-methyl- 7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 222 N2-(4-fluoro-3- A D 3.63/4365.2 methoxyphenyl)-N4-methyl- 7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 223 N4-methyl-7-phenyl-N2- A D3.12/4 319.2 (pyrimidin-5-yl)-6,7- dihydro-5H- cyclopenta[d]pyrimidine-2,4-diamine 224 N4-methyl-7-phenyl-N2- A D 2.85/4 318.2(pyridin-4-yl)-6,7-dihydro- 5H- cyclopenta[d]pyrimidine- 2,4-diamine 2254-(4-(methylamino)-7- A D 3.57/4 342.2 phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- ylamino)benzonitrile 226 4-(4-(methylamino)-7-A C 2.94/4 342.1 phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-ylamino)benzonitrile 227 4-(4-(methylamino)-7- A C 2.92/4 342.1phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2- ylamino)benzonitrile228 2-(4-(methylamino)-7- A E 2.64/8 342.2 phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- ylamino)benzonitrile 229 4-(4-(methylamino)-7-A E 5.73/8 392.2 phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-ylamino)-1-naphthonitrile 230 5-(4-(methylamino)-7- A E 4.54/8 343.2phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2- ylamino)picolinonitrile231 2-(4-(4-(methylamino)-7- A E 4.65/8 356.2 phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- ylamino)phenyl)acetonitrile 2322-(4-(methylamino)-7- A E 4.57/8 382.2 phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- ylamino)-1H- benzo[d]imidazole-5- carbonitrile233 3-(4-(methylamino)-7- B E 4.37/8 342.1 phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- ylamino)benzonitrile 234N2-(4-tert-butylphenyl)-N4- B E 5.47/8 373.2 methyl-7-phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine- 2,4-diamine 235 N4-methyl-N2-(4- BE 3.79/8 395.1 (methylsulfonyl)phenyl)-7- phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 236 N4-methyl-7-phenyl-N2-(4- B E5.13/8 400.8 (trifluoromethoxy)phenyl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 237 4-(4-(methylamino)-7- B E4.47/8 367.2 phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-ylamino)phthalonitrile 238 4-(4-(methylamino)-7- B E 4.90/8 410.1phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2- ylamino)-2-(trifluoromethyl)benzonitrile 239 N4-methyl-7-phenyl-N2-(4- B E 5.13/8385.1 (trifluoromethyl)phenyl)-6,7- dihydro-5H- cyclopenta[d]pyrimidine-2,4-diamine 240 5-(4-(methylamino)-7- B E 3.89/8 371.2phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-ylamino)-2,3-dihydro-1H- inden-1-one 241 2-(4-(methylamino)-7- B E4.08/8 357.2 phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-ylamino)-1H-imidazole-4,5- dicarbonitrile 242 2-bromo-5-(4- B E 4.89/8420.1 (methylamino)-7-phenyl-6,7- dihydro-5H- cyclopenta[d]pyrimidin-2-ylamino)benzonitrile 243 N,N-dimethyl-4-(4- B E 3.50/8 388.2(methylamino)-7-phenyl-6,7- dihydro-5H- cyclopenta[d]pyrimidin-2-ylamino)benzamide 244 1-(4-(4-(methylamino)-7- B E 4.91/8 410.2phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-ylamino)phenyl)cyclopentanecarbonitrile 245 N4-methyl-7-phenyl-N2- B E4.14/8 372.2 (1,2,3,4- tetrahydroisoquinolin-6-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 246 4-(4-(methylamino)-7- B E5.04/8 426.1 phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-ylamino)-2- (trifluoromethoxy)benzonitrile 247 1-(4-(4-(methylamino)-7-B C 3.30/4 382.3 phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-ylamino)phenyl)cyclopropanecarbonitrile 248 1-(2-methoxy-4-(4- B C3.06/4 427.1 (methylamino)-7-phenyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-2- ylamino)phenylamino)cyclopropanecarbonitrile249 N4-methyl-N2-(2-methyl- A B 1.75/2 370.31H-indol-5-yl)-7-phenyl-6,7- dihydro-5H- cyclopenta[d]pyrimidine-2,4-diamine 250 N2-(benzofuran-5-yl)-N4- A B 1.85/2 357.2methyl-7-phenyl-6,7- dihydro-5H- cyclopenta[d]pyrimidine- 2,4-diamine251 N2-(1H-indol-5-yl)-N4- A B 1.68/2 356.3 methyl-7-phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine- 2,4-diamine 252 N4-methyl-N2-(2- AB 1.73/2 372.3 methylbenzo[d]oxazol-6-yl)- 7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 253 N2-(1H-benzo[d]imidazol-6- A B1.47/2 357.2 yl)-N4-methyl-7-phenyl-6,7- dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 254 N4-methyl-N2-(1-methyl- A B1.82/2 370.3 1H-indol-5-yl)-7-phenyl-6,7- dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 255 N4-methyl-N2-(2- A B 1.78/2388.2 methylbenzo[d]thiazol-6-yl)- 7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 256 N2-(4-bromo-3- A A 2.63/4425.0/ methoxyphenyl)-N4-methyl- 427.0 7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine Coupling Method A^(a): The methodas described in Example 8. Coupling Method B^(a): The two componentswere heated at 100° C. in 1:1 HOAc/Dioxane. Analysis was conducted onone of the following columns^(b): LC Method A^(b): Phenomenex Luna 3X5095/5 to 5/95 water/MeOH, 0.1% TFA LC Method B^(b): Phenomenex Luna 2X5095/5 to 5/95 water/CH3CN, 0.1% NH4OAc LC Method C^(b): Phenomenex Luna2X50 95/5 to 5/95 water/MeOH, 0.1% TFA LC Method D^(b): Waters 2X50 95/5to 5/95 water/MeOH, 0.1% NH4OAc LC Method E^(b): Supelco Ascentis Exp95/5 to 5/95 water/CH3CN, 0.1% NH4OAc LC Retention Times^(c) arereported along with the gradient run time (rt/grt).

Example 2571-(4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)ethanone

A mixture of Example 256 (20 mg, 0.047 mmol),tributyl(1-ethoxyvinyl)stannane (67.9 mg, 0.188 mmol) and Tetrakis (5.43mg, 4.70 μmol) in toluene (188 μL) was heated at 80° C. for 12 hrs. Thecrude product was purified by prep HPLC. The resulting product wastreated with HCl(0.8 eq.) in acetone (0.285 M) and stirred at RTovernight. The mixture was concentrated and added EtOAc, washed withwater, brine, dried over Na2SO4 and concentrated to get1-(2-methoxy-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)ethanone(4 mg, 10.3 μmol, 22% yield). LC-MS (M+H)⁺=389.2 ¹H NMR (500 MHz, MeOD)δ ppm 7.74 (d, J=8.55 Hz, 1H) 7.66 (s, 1H) 7.36-7.49 (m, 3H) 7.19-7.36(m, 2H) 7.08 (dd, J=8.55, 1.83 Hz, 1H) 4.45 (br. s., 1H) 3.86-3.98 (m,3H) 3.16-3.24 (m, 3H) 2.93 (br. s., 1H) 2.73-2.86 (m, 2H) 2.53-2.63 (m,3H) 2.11-2.23 (m, 1H).

Example 258N2-(4-cyclopropylphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

To a solution of the fluorinated analog of Example 256 (150 mg, 0.338mmol) in Toluene (Ratio: 20, Volume: 1611 μl) was addedCyclopropylboronic acid (37.8 mg, 0.440 mmol), PdOAc2 (3.80 mg, 0.017mmol), Tricyclohexylphosphine (9.49 mg, 0.034 mmol), Potassiumorthophosphate (251 mg, 1.184 mmol), and Water (Ratio: 1.000, Volume: 81μl). The resulting mixture was brought to 110° C. and stirred overnight.The reaction mixture was diluted with EtOAc (5 mL), washed with water (2mL), brine (2 mL), dried over MgSO4, filtered and concentrated in vacuo.Purification by flash chromatography (Silica, EtOAc/Hexanes) gaveN2-(4-cyclopropyl-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(15 mg, 0.037 mmol, 10.96% yield). LC-MS (M+H)⁺=405.1 ¹H NMR (500 MHz,MeOD) δ ppm 7.60 (d, J=1.83 Hz, 1H) 7.19 (dd, J=7.93, 5.80 Hz, 2H)6.97-7.14 (m, 3H) 6.69-6.78 (m, 1H) 4.05-4.22 (m, 2H) 3.62-3.71 (m, 3H)2.98-3.11 (m, 3H) 2.72-2.85 (m, 1H) 2.55-2.72 (m, 2H) 1.90-2.05 (m, 2H)1.26 (t, J=7.17 Hz, 1H) 0.73-0.86 (m, 1H) 0.46-0.61 (m, 1H).

Example 259N2-(4-ethynylphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The mixture of tributyl(ethynyl)stannane (53.3 mg, 0.169 mmol), thefluorinated analog of Example 256 (50 mg, 0.113 mmol) and Tetrakis (10.0mg, 0.011 mmol) in toluene (226 μL) was heated at 110° C. for 2 h, andthen the solvent was removed in vacuo. The residue was purified by prepHPLC to getN2-(4-ethynyl-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(1.5 mg, 3.86 μmol). LC-MS (M+H)⁺=389.2 ¹H NMR (500 MHz, CHLOROFORM-d) δppm 7.86 (s, 1H) 7.31 (d, J=8.55 Hz, 2H) 7.16 (dd, J=7.78, 5.65 Hz, 3H)7.01 (t, J=8.70 Hz, 2H) 6.71 (br. s., 1H) 4.52 (br. s., 1H) 3.71 (s, 3H)3.15 (d, J=4.88 Hz, 3H) 2.67 (d, J=9.77 Hz, 3 H) 1.95-2.14 (m, 1H).

Example 2607-(4-fluorophenyl)-N4-methyl-N2-(4-(prop-1-ynyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The mixture of tributyl(prop-1-ynyl)stannane (55.7 mg, 0.169 mmol), thefluorinated analog of Example 256 (50 mg, 0.113 mmol) and Tetrakis (10.0mg, 0.011 mmol) in toluene (226 μL) was heated at 110° C. for 2 h, andthen the solvent was removed in vacuo. The residue was purified by prepHPLC to get7-(4-fluorophenyl)-N2-(3-methoxy-4-(prop-1-ynyl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(2.0 mg, 4.97 μmol). LC-MS (M+H)⁺=403.3 ¹H NMR (400 MHz, CHLOROFORM-d) δppm 7.80 (d, J=1.76 Hz, 1H) 7.10-7.23 (m, 3H) 6.93-7.08 (m, 2H) 6.73 (s,1H) 4.51 (br. s., 1H) 4.05-4.29 (m, 1H) 3.70 (s, 3H) 3.14 (d, J=4.77 Hz,3H) 2.56-2.79 (m, 3H) 2.09-2.14 (m, 3H) 1.99-2.09 (m, 1H).

Example 261N2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The mixture of 2-methylpyridin-4-ylboronic acid (25.1 mg, 0.183 mmol),Example 256 (26 mg, 0.061 mmol), Tetrakis (14.1 mg, 0.012 mmol) andsodium carbonate (13.0 mg, 0.122 mmol) in toluene (255 μL)/water (50 μL)was heated at 150° C. for 5 h, and then the solvent was removed invacuo. The residue was purified by prep HPLC to getN2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(5.0 mg, 0.011 mmol). LC-MS (M+H)⁺=438.2 ¹H NMR (500 MHz, MeOD) δ ppm8.60 (br. s., 1H) 8.06-8.19 (m, 2H) 7.75 (d, J=1.83 Hz, 1H) 7.60-7.70(m, 1H) 7.38-7.49 (m, 2H) 7.22-7.38 (m, 4H) 4.43-4.57 (m, 1 H) 3.86-3.99(m, 3H) 3.17-3.26 (m, 3H) 2.89-3.01 (m, 1H) 2.73-2.89 (m, 5H) 2.19 (dt,J=9.16, 6.87 Hz, 1H).

Example 262N2-(3-methoxy-4-(pyridin-4-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The mixture of 4-(tributylstannyl)pyridine (69.2 mg, 0.188 mmol),Example 256 (20 mg, 0.047 mmol) and Tetrakis (5.43 mg, 4.70 μmol) intoluene (196 μL)/water (39 μL) was heated at 100° C. for 12 h, and thenthe solvent was removed in vacuo. The residue was purified by prep HPLCto getN2-(3-methoxy-4-(pyridin-4-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(4.0 mg, 9.44 μmol). LC-MS (M+H)⁺=424.2 ¹H NMR (500 MHz, MeOD) δ ppm8.20-8.90 (m, 4H) 7.74 (d, J=1.83 Hz, 1H) 7.62-7.70 (m, 1H) 7.39-7.47(m, 2H) 7.23-7.37 (m, 4H) 4.43-4.54 (m, 1H) 3.94 (s, 3H) 3.22 (s, 3H)2.89-3.01 (m, 1H) 2.75-2.87 (m, 2H) 2.12-2.29 (m, 1H).

Example 263N2-(3-methoxy-4-(pyridin-3-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

The mixture of 3-(tributylstannyl)pyridine (55.4 mg, 0.150 mmol),Example 256 (16 mg, 0.061 mmol) and Tetrakis (4.35 mg, 3.76 μmol) intoluene (188 μL) was heated at 100° C. for 12 h, and then the solventwas removed in vacuo. The residue was purified by prep HPLC to getN2-(3-methoxy-4-(pyridin-3-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(4.0 mg, 9.44 μmol). LC-MS (M+H)⁺=424.2 ¹H NMR (500 MHz, MeOD) δ ppm8.52 (br. s., 2H) 7.67-7.76 (m, 2H) 7.55-7.64 (m, 1H) 7.43-7.50 (m, 1H)7.41 (d, J=7.32 Hz, 2H) 7.32-7.37 (m, 1H) 7.17-7.31 (m, 3H) 4.41-4.56(m, 1H) 3.88 (s, 3H) 3.16-3.28 (m, 3H) 2.88-3.02 (m, 1H) 2.73-2.88 (m,2H) 2.09-2.26 (m, 1H).

BIOLOGICAL METHODS Cellular Assays for Inhibition of Aβ1-40 and Aβ1-42production

H4 cells stably transfected with APP751 containing the Swedish mutation(H4 APP751 SWE clone 8.20, developed at BMS) were maintained in logphase through twice weekly passage at a 1:20 split. For IC₅₀determinations, 30 μl cells (1.5×10⁴ cells/well) in DMEM mediacontaining 0.0125% BSA (Sigma A8412) were plated directly into 384-wellcompound plates (Costar 3709) containing 0.1 μl serially dilutedcompound in DMSO. Following incubation for 19 h in 5% CO₂ at 37° C.,plates were briefly centrifuged (1000 rpm, 5 min). A 10 μl aliquot fromeach well was transferred to a second assay plate (Costar 3709) for Aβ40measurements. Antibody cocktails were freshly prepared by dilution into40 mM Tris-HCl (pH 7.4) with 0.2% BSA and added to assay plates. ForAβ42 measurements, antibodies specific for the Aβ42 neoepitope (565,developed at BMS; conjugated to the Wallac reagent (Perkin Elmer)) andthe N-terminal sequence of Aβ peptide (26D6, developed at SIBIA;conjugated to APC (Perkin Elmer)) were mixed and 20 μl of the mixturewas added to each well of the incubated cell plate yielding a finalconcentration of 0.8 ng/well 565 and 75 ng/well 26D6. For the Aβ40measurements, antibodies specific for the Aβ40 neoepitope (TSD,developed at BMS; conjugated to the Wallac reagent (Perkin Elmer)) and26D6 as described above were mixed and 20 μl of the mixture was added tothe 10 μl aliquots which had been removed previously from the cell plateyielding a final concentration of 1.6 ng/well TSD and 17.5 ng/well 26D6.Assay plates containing antibodies were sealed with aluminum foil andincubated overnight at 4° C. Signal was determined using a Viewluxcounter (Perkin Elmer) and IC₅₀ values determined using curve fitting inCurveMaster (Excel Fit based).

The activity of representative compounds of the present disclosure,based on Aβ42 cellular IC₅₀ values in H4 APP751 SWE clone 8.20, areillustrated in Table 1 (below).

TABLE 1 Compound of Activity Compound of Activity Example Rating^(a)Example Rating^(a)  1 +++  85 +++  2 +++  86 ++  3 ++  87 60 nM  3A +++ 88 ++  3B ++  88A 4.5 nM   4 +++  88B ++  4A +++  89 ++  4B ++  90A ++ 5 +++  90B 270 nM   5A +++  91A +++  5B ++  91B +  6 ++  92 ++  6A +++ 93 20 nM  6B ++  94 +++  7A +++  94A +++  7B ++  94B ++  8 +++  95 +++ 9 8.1 nM   95A +++  10 +++  95B ++  11 +++  96 +++  11A 3.8  96A +++ 11B +++  96B 4.6 nM   12 +++  97 +++  12A +++  97A +++  13 −  97B ++ 14 −  98 ++  15 ++  98A +++  16 ++  98B ++  16A +++  99 19 nM  16B + 99A ++  17 ++  99B 190 nM   17A 120 nM  100 +++  17B ++ 100A 4.7 nM  18 ++ 100B ++  18A 8.8 nM  101 ++  18B ++ 101A +++  19 ++ 101B ++  19A++ 102 +++  19B 59 nM 102A +++  20 +++ 102B ++  20A +++ 103 +++  20B ++103A +++  21 ++ 103B ++  21A ++ 104 ++  21B + 105 8.8 nM   23 ++ 106 ++ 23A ++ 107 ++  23B + 107A ++  24 ++ 107B +  24A ++ 108 20 nM  24B 200nM  109A +++  25 ++ 109B +++  26 +++ 110A +++  26A ++ 110B ++  26B ++111 35 nM  27 ++ 112 +++  28 ++ 112A +++  28A ++ 112B ++  29 ++ 113 5.7nM   29A ++ 113A +++  29B ++ 113B ++  30 ++ 114 +++  30A ++ 114A ++  30B230 nM  114B +  31 + 115 +++  32 ++ 115A +++  33 100 nM  115B ++  34 ++116 ++  35 +++ 116A +++  36 ++ 116B +  37 +++ 117 45 nM  38 ++ 117A ++ 38A 12 nM 117B +  38B ++ 118 ++  39 ++ 118A +++  39B + 118B +  40A +++119 ++  40B + 119A 7.4 nM   41 ++ 119B +  41A ++ 120 ++  41B ++ 120A +++ 41C ++ 120B +  41D ++ 121 ++  42 ++ 121A +++  42A +++ 121B 120 nM   43+++ 122A +++  44 13 nM 123A ++  44A +++ 123B 370 nM   45A ++ 124 ++  45B2.5 nM  124A +++  45C ++ 124B ++  45D +++ 125 ++  46 +++ 126 ++  46A +++127 ++  46B ++ 127A +++  47 +++ 127B ++  48 18 nM 128 +  48A +++ 129 ++ 48B 130 nM  129A +++  49 +++ 130 +++  49A +++ 130A +++  49B ++ 131 ++ 50 +++ 131A +++  50A +++ 132 ++  50B ++ 132A 15 nM  51 4.5 nM  133 ++ 51A +++ 133A +++  51B +++ 134 +++  52 ++ 134A 3.6 nM   52A +++ 135 ++ 52B ++ 135A ++  53 ++ 136 +++  53A +++ 136A +++  53B ++ 137 11 nM  54++ 137A +++  54A ++ 138 ++  54B +++ 138A +++  55 ++ 139 ++  55B ++ 139A++  56 ++ 140 ++  56A +++ 140A +++  56B ++ 141 ++  57A 14 nM 141A +++ 57B + 142 ++  58A +++ 143 ++  58B 120 nM  143B 430 nM   59 ++ 144 ++ 59A +++ 144B 540 nM   60 +++ 145 ++  60A 5.6 nM  146 ++  60B ++ 147 ++ 61 ++ 148A +++  61A +++ 149 ++  61B ++ 150 ++  62 ++ 151 +++  62A +++151A +++  62B 86 nM 152 ++  63 ++ 153 ++  63A ++ 154 ++  63B + 154A +++ 64 ++ 155A +++  64A +++ 156 +++  64B ++ 156A 9.8 nM   65 ++ 157 ++  65A5.3 nM  157A ++  65B 160 nM  158 ++  66 ++ 159 ++  66A + 160 ++  66B +++161 +  67 ++ 162 ++  67A ++ 162A ++  67B 540 nM  163A +++  68 ++ 164A ++ 69 ++ 165 ++  69A +++ 165A ++  69B + 165B 180 nM   70 +++ 166 +  70A+++ 167A 26 nM  70B ++ 168A +++  71 ++ 169 ++  71A +++ 169A +++  71B ++170 ++  72 +++ 170A +++  73 3.8 nM  171 16 nM  74A ++ 171A ++  75 ++172A +++  75A +++ 172B +  75B ++ 173 490 nM   76 ++ 174 ++  77 ++ 175 ++ 78 ++ 175A +++  78A 19 nM 176 +++  78B ++ 176A +++  79A 5.8 nM  176B+++  79B ++ 177 ++  80 ++ 178 +++  80A ++ 179 ++  81 ++ 180 ++  82 ++181 ++  82A +++ 181A +++  82B ++ 181B 50 nM  83 ++ 182 ++  83A +++ 182A+++  83B ++ 182B ++  84 ++ 183 11 nM  84A ++ 183A +++  84B 290 nM  183B++ 184 ++ 211 +++ 185 ++ 212 33 nM 186 ++ 213 insol 187 ++ 214 77 nM187A ++ 215A {circumflex over ( )} 187B ++ 215B 173 nM  188 19 nM 216{circumflex over ( )} 189 +++ 217 {circumflex over ( )} 189A +++ 2183700 nM  189B ++ 219 {circumflex over ( )} 190 37 nM 220 550 nM  191 ++221 {circumflex over ( )} 191A ++ 222 {circumflex over ( )} 191B 96 nM223 11000 nM   192 64 nM 224 {circumflex over ( )} 192A 170 nM  225 18nM 192B 16 nM 226 + 193 ++ 193B ++ 193A + 227 12 nM 194 ++ 228{circumflex over ( )} 194A ++ 229 {circumflex over ( )} 194B 175 nM  23042 nM 195 17 nM 231 + 195A 26 nM 232 {circumflex over ( )} 195B + 233{circumflex over ( )} 196 ++ 234 {circumflex over ( )} 196A +++ 235 +196B 54 nM 236 {circumflex over ( )} 197 16 nM 237 29 nM 197A 60 nM238 + 197B +++ 239 + 198 ++ 240 Insol 198A + 241 Insol 198B 15 nM 242 67nM 199 ++ 243 + 199A + 244 {circumflex over ( )} 199B +++ 245{circumflex over ( )} 200 ++ 246 31 nM 200A ++ 247 + 200B ++ 248{circumflex over ( )} 201 5.3 nM  249 {circumflex over ( )} 201A 10 nM250 {circumflex over ( )} 201B ++ 251 {circumflex over ( )} 202 +++ 252{circumflex over ( )} 203 19 nM 253 5900 nM  203A +++ 254 1000 nM  203B++ 255 {circumflex over ( )} 204 19 nM 256 97 nM 204A 19 nM 257 ++204B + 258 {circumflex over ( )} 205 ++ 259 940 nM  206 15 nM 260 860nM  207 + 261 +++ 208 ++ 262 +++ 209 +++ 263 32 nM 210 61 nM^(a)Activity based on Aβ42 cellular IC₅₀ values in H4 APP751 SWE clone8.20. +++ = 1.5 nM-0.0099 M ++ = 0.010-0.100 μM + = 0.100-1.0 μM{circumflex over ( )} = >1.0 μM

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein A is a five- orsix-membered heteroaromatic ring containing from one to threeheteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein said heteroaromatic ring is optionally substituted with one ortwo groups selected from halo, haloC₁₋₆alkyl, hydroxy, amino,C₁₋₆alkoxy, and C₁₋₆alkyl; B is selected from phenyl and pyridinyl,wherein the phenyl and pyridinyl are optionally substituted with one ortwo substituents independently selected from C₁₋₆alkoxy, C₁₋₆alkyl,C₁₋₃alkylamino-C₁₋₆alkoxy, cyano, C₁₋₃dialkylamino-C₁₋₆alkoxy, halo,haloC₁₋₆alkoxy, haloC₁₋₆alkyl, hydroxy, methylamino, and amino; D isselected from

“

” denotes the point of attachment to the nitrogen atom of the parentmolecule; “

” denotes the point of attachment to the ‘E’ moiety; R^(a) is selectedfrom hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, and hydroxy; R^(b) is—NR^(x)R^(y), wherein R^(x) and R^(y) are independently selected fromhydrogen, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkoxycarbonyl,C₁₋₆alkyl, C₃₋₇cycloalkyl, (C₃₋₇cycloalkyl)C₁₋₄alkyl, hydroxyC₁₋₄alkyl,and trideuteromethyl, wherein the alkyl part of the(C₃₋₇cycloalkyl)C₁₋₄alkyl can be optionally substituted with aC₁₋₄alkoxy group; or, R^(x) and R^(y), together with the nitrogen atomto which they are attached, form a four- to seven-membered monocyclic orbicyclic ring optionally containing one double bond and optionallycontaining one additional heteroatom selected from O, NR^(z), and S;wherein R^(z) is selected from hydrogen, C₁₋₆alkyl, andC₁₋₄alkoxycarbonyl; and wherein the ring is optionally substituted withone or two substituents independently selected from C₁₋₆alkoxy,C₁₋₆alkyl, halo, haloC₁₋₄alkyl, hydroxy, —NR^(f)R^(g), oxo, spirocyclicdioxolanyl; wherein R^(f) and R^(g) are independently selected fromhydrogen, C₁₋₄alkoxycarbonyl, and C₁₋₆alkyl; R^(c) is selected fromhydrogen, C₁₋₄alkylsulfonyl, C₁₋₄alkylsulfonylamido, amino,C₁₋₆alkylamino, C₁₋₆dialkylamino, C₃₋₇cycloalkylamino, hydroxy, andC₁₋₄alkoxy; R^(d) is selected from hydrogen, C₁₋₆alkyl,C₁₋₄alkoxyC₁₋₄alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonyl,C₁₋₆alkylsulfonyl, C₃₋₇cycloalkylsulfonyl, C₃₋₇cycloalkylcarbonyl,C₁₋₆dialkylaminoC₁₋₄alkylcarbonyl, and haloC₁₋₄alkyl, wherein the alkylpart of the alkoxycarbonyl, the alkylcarbonyl, and the alkylsulfonyl areoptionally substituted with one substituent selected fromC₁₋₄dialkylamino, and C₁₋₄alkoxy; and E is selected from C₁₋₆alkyl,C₄₋₆cycloalkyl, (C₄₋₇cycloalkyl)C₁₋₄alkyl, benzyl, phenyl, and a five-to six-membered heteroaromatic ring containing one or two nitrogenatoms, wherein the phenyl, the phenyl part of the benzyl, and theheteroaromatic ring are each optionally substituted with one, two, orthree substituents independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,cyano, halo, halo C₁₋₆alkoxy, and haloC₁₋₆alkyl.
 2. A compound of claim1, or a pharmaceutically acceptable salt thereof, wherein A is afive-membered heteroaromatic ring containing from one to three nitrogenatoms; wherein said heteroaromatic ring is optionally substituted withone group selected from halo and C₁₋₆alkyl.
 3. A compound of claim 2, ora pharmaceutically acceptable salt thereof, wherein B is selected fromphenyl and pyridinyl, wherein the phenyl and pyridinyl are optionallysubstituted with one or two substituents independently selected fromC₁₋₆alkoxy and halo.
 4. A compound of claim 3, or a pharmaceuticallyacceptable salt thereof, wherein E is phenyl optionally substituted withone, two, or three substituents independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, cyano, halo, haloC₁₋₆alkoxy, and haloC₁₋₆alkyl.
 5. Acompound of claim 4, or a pharmaceutically acceptable salt thereof,wherein D is selected from


6. A compound of claim 5, or a pharmaceutically acceptable salt thereof,wherein R^(b) is —NR^(x)R^(y), wherein R^(x) and R^(y) are independentlyselected from hydrogen, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₆alkyl, C₃₋₇cycloalkyl,hydroxyC₁₋₄alkyl, and trideuteromethyl, wherein the alkyl part of the(C₃₋₇cycloalkyl)C₁₋₄alkyl can be optionally substituted with aC₁₋₄alkoxy group.
 7. A compound of claim 5, or a pharmaceuticallyacceptable salt thereof, wherein R^(b) is —NR^(x)R^(y), wherein R^(x)and R^(y), together with the nitrogen atom to which they are attached,form a four- to seven-membered monocyclic or bicyclic ring optionallycontaining one additional heteroatom selected from O and NR^(z); whereinR^(z) is selected from C₁₋₆alkyl, and C₁₋₄alkoxycarbonyl; and whereinthe ring is optionally substituted with one or two substituentsindependently selected from C₁₋₆alkoxy, C₁₋₆alkyl, halo, haloC₁₋₄alkyl,hydroxy, —NR^(f)R^(g), oxo, and spirocycle dioxolanyl; wherein R^(f) andR^(g) are independently selected from hydrogen, C₁₋₄alkoxycarbonyl, andC₁₋₆alkyl.
 8. A compound of claim 4, or a pharmaceutically acceptablesalt thereof, wherein D is selected from


9. A compound of claim 8, or a pharmaceutically acceptable salt thereof,wherein R^(b) is —NR^(x)R^(y), wherein R^(x) and R^(y) are independentlyselected from hydrogen, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₆alkyl, C₃₋₇cycloalkyl,hydroxyC₁₋₄alkyl, and trideuteromethyl, wherein the alkyl part of the(C₃₋₇cycloalkyl)C₁₋₄alkyl can be optionally substituted with aC₁₋₄alkoxy group.
 10. A compound of claim 8, or a pharmaceuticallyacceptable salt thereof, wherein R^(b) is —NR^(x)R^(y), wherein R^(x)and R^(y), together with the nitrogen atom to which they are attached,form a four- to seven-membered monocyclic or bicyclic ring optionallycontaining one additional heteroatom selected from O and NR^(z); whereinR^(z) is selected from C₁₋₆alkyl, and C₁₋₄alkoxycarbonyl; and whereinthe ring is optionally substituted with one or two substituentsindependently selected from C₁₋₆alkoxy, C₁₋₆alkyl, halo, haloC₁₋₄alkyl,hydroxy, —NR^(f)R^(g), oxo, and spirocycle dioxolanyl; wherein R^(f) andR^(g) are independently selected from hydrogen, C₁₋₄alkoxycarbonyl, andC₁₋₆alkyl.
 11. A compound of claim 4, or a pharmaceutically acceptablesalt thereof, wherein D is selected from


12. A compound of claim 11, or a pharmaceutically acceptable saltthereof, wherein R^(b) is —NR^(x)R^(y), wherein R^(x) and R^(y) areindependently selected from hydrogen, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₆alkyl,C₃₋₇cycloalkyl, hydroxyC₁₋₄alkyl, and trideuteromethyl, wherein thealkyl part of the (C₃₋₇cycloalkyl)C₁₋₄alkyl can be optionallysubstituted with a C₁₋₄alkoxy group.
 13. A compound of claim 11, or apharmaceutically acceptable salt thereof, wherein R^(b) is —NR^(x)R^(y),wherein R^(x) and R^(y), together with the nitrogen atom to which theyare attached, form a four- to seven-membered monocyclic or bicyclic ringoptionally containing one additional heteroatom selected from O andNR^(z); wherein R^(z) is selected from C₁₋₆alkyl, andC₁₋₄alkoxycarbonyl; and wherein the ring is optionally substituted withone or two substituents independently selected from C₁₋₆alkoxy,C₁₋₆alkyl, halo, haloC₁₋₄alkyl, hydroxy, —NR^(f)R^(g), oxo, andspirocycle dioxolanyl; wherein R^(f) and R^(g) are independentlyselected from hydrogen, C₁₋₄alkoxycarbonyl, and C₁₋₆alkyl.
 14. Acompound selected fromN2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;4-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;(S)-4-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;(R)-4-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(3-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(2-Fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;4-(4-amino-4-methylpiperidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-01;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-01;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-01;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-(methylamino)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-(methylamino)azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)azetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N²-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine);N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4,4-difluoropiperidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4-fluoro-5,6-dihydropyridin-1(2H)-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-(3-ethoxypropyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;3-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)propan-1-ol;7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-(1-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-trideuteromethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-((R)-1-methoxybutan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((S)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imiazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imiazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-8-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4,N4-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴,N⁴-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-N²-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-chlorophenyl)-N²-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-bromophenyl)-N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(4-bromophenyl)-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-2-methylpyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine;N⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine;N⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine;N⁴-ethyl-N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N⁴-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine;N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N4-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine;N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine;N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴,N⁴-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;(S)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;(R)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴,N⁴-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;4-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;(S)-4-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;(R)-4-(Azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,5-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N²-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-N⁴-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;(S)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;(R)—N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(2,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(2,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(2,4-difluorophenyl)-N⁴-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-7-allyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(3,5-difluorophenyl)-N4-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(3,4-difluorophenyl)-N4-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(3,4-difluorophenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;8-(3,4-difluorophenyl)-N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((R)-1-cyclopropylethyl)-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;4-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)benzonitrile;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-N⁴-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-phenyl-5,6,7,8-tetrahydroquinazolin-2-amine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-ethyl-8-(4-fluorophenyl)-N⁴-methyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N⁴,N⁴-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N⁴,N⁴-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N⁴,N⁴-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-6-(cyclopropylsulfonyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;Methyl2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate;(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(cyclopropyl)methanone;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxyethanone;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(dimethylamino)ethanone;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-6-(cyclopropylsulfonyl)-N4-ethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-(ethylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;6-(cyclopropylsulfonyl)-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;6-(cyclopropylsulfonyl)-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;cyclopropyl(4-(ethylamino)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone;cyclopropyl(4-(ethylamino)-2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)methanone;N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,N4-dimethyl-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4-methyl-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,6-diethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,7-diethyl-8-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine;methyl2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-(4-fluorophenyl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-(4-fluorophenyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethanone;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine;N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)—N²-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N⁴-trideuteromethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-8-phenyl-7,8-dihydroquinazolin-8-ol;2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-8-phenyl-5,6,7,8-tetrahydroquinazolin-8-ol;2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol;(6S,7S)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-6-ol;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-chloroazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-fluoroazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-methoxyazetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylazetidine-3-carbonitrile;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-ethoxyazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(5-oxa-2-azaspiro[3.4]octan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylazetidin-3-ol;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-fluoro-3-methylazetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-methoxy-3-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;7-(4-fluorophenyl)-4-(3-methoxy-3-methylazetidin-1-yl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;7-(2,4-difluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(S)-7-(2,4-difluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;(R)-7-(2,4-difluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;6-(2,2-difluoroethyl)-N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;6-(2,2-difluoroethyl)-N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-N2-(3-methoxy-4-(4-chloro-1H-13-imidazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;N4-ethyl-N2-(3-methoxy-4-(4-chloro-1H-13-imidazol-1-yl)phenyl)-8-phenyl-6-(2,2-difluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;8-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;8-(4-fluorophenyl)-N2-(3-methoxy-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine;(±)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one;(E)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-oneO-methyl oxime;2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-ol;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine;1-(2-methoxy-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)-1H-imidazole-4-carbonitrile;N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-one;4-(8-(4-fluorophenyl)-4-(methylamino)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)benzonitrile;N2-(4-(4-(difluoromethyl)-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylmethanesulfonamide;N-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methanesulfonamide;N-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylacetamide;N-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-acetamide;N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-(5-isopropyl-2-methylphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;4-(4-(5-isopropyl-2-methylphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile;N4-methyl-N2-(2-methylpyridin-4-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-fluorophenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(3,5-difluorophenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-chloro-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-bromo-2-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-fluoro-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N4-methyl-7-phenyl-N2-(pyrimidin-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N4-methyl-7-phenyl-N2-(pyridin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile;4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile;4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile;2-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile;4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)-1-naphthonitrile;5-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)picolinonitrile;2-(4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)acetonitrile;2-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)-1H-benzo[d]imidazole-5-carbonitrile;3-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile;N2-(4-tert-butylphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N4-methyl-N2-(4-(methylsulfonyl)phenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N4-methyl-7-phenyl-N2-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phthalonitrile;4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)-2-(trifluoromethyl)benzonitrile;N4-methyl-7-phenyl-N2-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;5-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)-2,3-dihydro-1H-inden-1-one;2-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)-1H-imidazole-4,5-dicarbonitrile;2-bromo-5-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile;N,N-dimethyl-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzamide;1-(4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)cyclopentanecarbonitrile;N4-methyl-7-phenyl-N2-(1,2,3,4-tetrahydroisoquinolin-6-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)-2-(trifluoromethoxy)benzonitrile;1-(4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)cyclopropanecarbonitrile;1-(2-methoxy-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenylamino)cyclopropanecarbonitrile;N4-methyl-N2-(2-methyl-1H-indol-5-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(benzofuran-5-yl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(1H-indol-5-yl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N4-methyl-N2-(2-methylbenzo[d]oxazol-6-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(1H-benzo[d]imidazol-6-yl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N4-methyl-N2-(1-methyl-1H-indol-5-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N4-methyl-N2-(2-methylbenzo[d]thiazol-6-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-bromo-3-methoxyphenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;1-(4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)ethanone;N2-(4-cyclopropylphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(4-ethynylphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;7-(4-fluorophenyl)-N4-methyl-N2-(4-(prop-1-ynyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;N2-(3-methoxy-4-(pyridin-4-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine,andN2-(3-methoxy-4-(pyridin-3-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine;or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition for the treatment of disorders responsive to the reductionof β-amyloid peptide production comprising a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof, in association with a pharmaceutically acceptable carrier ordiluent.
 16. A method for the treatment of disorders responsive to thereduction of β-amyloid peptide production in a mammal in need thereof,which comprises administering to said mammal a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof.
 17. A method of claim 16 wherein said disorder is selected fromAlzheimer's Disease (AD), Down Syndrome, mild cognitive impairment(MCI), cerebral amyloid angiopathy (CAA), dementia with Lewy bodies(DLB), amyotrophic lateral sclerosis (ALS-D), inclusion body myositis(IBM), age-related macular degeneration, and cancer.
 18. A method ofclaim 17 wherein said disorder is selected from Alzheimer's Disease andDown Syndrome.
 19. A method of claim 18 wherein said disorder isAlzheimer's Disease.